1,3,4-thiadiazoles and 1,3,4-Oxadiazoles as αv β3 antagonists

ABSTRACT

This invention relates to 1,3,4-thiadiazoles and 1,3,4-Oxadiazoles of Formula (I) which are useful as antagonists of α v  β 3  and related integrin receptors, to pharmaceutical compositions containing such compounds, alone or in combination with other therapeutic agents, for the inhibition of cell adhesion and the tretment of angioginic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other cell aggregation-related conditions.

This application claims the benefit of U.S. Provisional Application No.60/066,561, filed Nov. 26, 1997.

FIELD OF THE INVENTION

The present invention relates generally to 1,3,4-thiadiazoles and1,3,4-Oxadiazoles which are useful as antagonists of the α_(v) β₃ andrelated integrin receptors, to pharmaceutical compositions containingsuch compounds, processes for preparing such compounds, and to methodsof using these compounds, alone or in combination with other therapeuticagents, for the inhibition of cell adhesion and the treatment ofangiogenic disorders, inflammation, bone degradation, tumors,metastases, thrombosis, and other cell aggregation-related conditions.

BACKGROUND OF THE INVENTION

Discloses angiogenesis or neovascularization is critical for normalphysiological processes such as embryonic development and wound repair(Folkman and Shing, J. Biol. Chem. 1992, 267:10931-10934; D'Amore andThompson, Ann. Rev. Physiol. 1987, 49:453-464). However, angiogenesisoccurs pathologically, for example, in ocular neovascularization(leading to diabetic retinopathy, neovascular glaucoma, retinal veinocclusion and blindness), in rheumatoid arthitis and in solid tumors(Folkman and Shing, J. Biol. Chem., 1992, 267:10931-10934; Blood andZetter, Biochim. Biophys. Acta., 1990, 1032:89-118).

Tumor dissemination, or metastasis, involves several distinct andcomplementary components, including the penetration and transversion oftumor cells through basement membranes and the establishment ofself-sustaining tumor foci in diverse organ systems. To this end, thedevelopment and proliferation of new blood vessels, or angiogenesis, iscritical to tumor survival. Without neovascularization, tumor cells lackthe nourishment to divide and will not be able to leave the primarytumor site (Folkman and Shing, J. Biol. Chem., 1992, 267:10931-10934).

Inhibition of angiogenesis in animal models of cancer has been shown toresult in tumor growth suppression and prevention of metastatic growth.Many angiogenic inhibitors have been directed toward blocking initialcytokine-dependent induction of new vessel growth, e.g. antibodies toendothelial cell growth factors. However, these approaches areproblematic because tumor and inflammatory cells can secrete multipleactivators of angiogenesis (Brooks et al., Cell, 1994, 79:1157-1164).Therefore, a more general approach that would allow inhibition ofangiogenesis due to a variety of stimuli would be of benefit.

The integrin α_(v) β₃ is preferentially expressed on angiogenic bloodvessels in chick and man (Brooks et al., Science, 1994, 264:569-571;Enenstein and Kramer, J. Invest. Dermatol., 1994, 103:381-386). Integrinα_(v) β₃ is the most promiscuous member of the integrin family, allowingendothelial cells to interact with a wide variety of extracellularmatrix components (Hynes, Cell, 1992, 69:11-25). These adhesiveinteractions are considered to be critical for angiogenesis sincevascular cells must ultimately be capable of invading virtually alltissues.

While integrin α_(v) β₃ promotes adhesive events important forangiogenesis, this receptor also transmits signals from theextracellular environment to the intracellular compartment (Leavesley etal., J. Cell Biol., 1993, 121:163-170, 1993). For example, theinteraction between the α_(v) β₃ integrin and extracellular matrixcomponents promotes a calcium signal required for cell motility.

During endothelium injury, the basement membrane zones of blood vesselsexpress several adhesive proteins, including but not limited to vonWillebrand factor, fibronectin, and fibrin. Additionally, severalmembers of the integrin family of adhesion receptors are expressed onthe surface of endothelial, smooth muscle and on other circulatingcells. Among these integrins is α_(v) /β₃, the endothelial cell,fibroblast, and smooth muscle cell receptor for adhesive proteinsincluding von Willebrand factor, fibrinogen (fibrin), vitronectin,thrombospondin, and osteopontin. These integrins initiate acalcium-dependent signaling pathway that can lead to endothelial cell,smooth muscle cell migration and, therefore, may play a fundamental rolein vascular cell biology.

Recently, an antibody to the α_(v) β₃ integrin has been developed thatinhibits the interaction of this integrin with agonists such asvitronectin (Brooks et al., Science, 1994, 264:569-571). Application ofthis antibody has been shown to disrupt ongoing angiogenesis on thechick chorioallantoic membrane (CAM), leading to rapid regression ofhistologically distinct human tumor transplanted onto the CAM (Brooks etal., Cell, 1994, 79:1157-1164). In this model, antagonists of the α_(v)β₃ integrin induced apoptosis of the proliferating angiogenic vascularcells, leaving pre-existing quiescent blood vessels unaffected. Thus,α_(v) β₃ integrin antagonists have been shown to inhibit angiogenesis.Based on this property, therapeutic utility of such agents is expectedin human diseases such as cancer, rheumatoid arthritis and ocularvasculopathies (Folkman and Shing, J. Biol. Chem., 1992,267:10931-10934).

Increasing numbers of other cell surface receptors have been identifiedwhich bind to extracellular matrix ligands or other cell adhesionligands thereby mediating cell-cell and cell-matrix adhesion processes.These receptors belong to a gene superfamily called integrins and arecomposed of heterodimeric transmembrane glycoproteins containing α- andβ-subunits. Integrin subfamilies contain a common β-subunit combinedwith different α-subunits to form adhesion receptors with uniquespecificity. The genes for eight distinct β-subunits have been clonedand sequenced to date.

Two members of the β1 subfamily, α4/β1 and α5/β1 have been implicated invarious inflammatory processes. Antibodies to α4 prevent adhesion oflymphocytes to synovial endothelial cells in vitro, a process which maybe of importance in rheumatoid arthritis (VanDinther-Janssen et al., J.Immunol., 1991, 147:4207-4210). Additional studies with monoclonalanti-α4 antibodies provide evidence that α4/β1 may additionally have arole in allergy, asthma, and autoimmune disorders (Walsh et al., J.Immunol., 1991, 146:3419; Bochner et al., J. Exp. Med., 1991 173:1553;Yednock et al., Nature, 1992, 356:63-66). Anti-α4 antibodies also blockthe migration of leukocytes to the site of inflammation (Issedutz etal., J. Immunol., 1991, 147:4178-4184).

The α_(v) /β₃ heterodimer is a member of the 3 integrin subfamily andhas been described on platelets, endothelial cells, melanoma, smoothmuscle cells, and osteoclasts (Horton and Davies, J. Bone Min. Res.1989, 4:803-808; Davies et al., J. Cell. Biol. 1989, 109:1817-1826;Horton, Int. J. Exp. Pathol., 1990, 71:741-759). Like GPIIb/IIIa, thevitronectin receptor binds a variety of RGD-containing adhesive proteinssuch as vitronectin, fibronectin, VWF, fibrinogen, osteopontin, bonesialo protein II and thrombosponden in a manner mediated by the RGDsequence. A key event in bone resorption is the adhesion of osteoclaststo the matrix of bone. Studies with monoclonal antibodies haveimplicated the α_(v) /β₃ receptor in this process and suggest that aselective α_(v) /β₃ antagonist would have utility in blocking boneresorption (Horton et al., J. Bone Miner. Res., 1993, 8:239-247;Helfrich et al., J. Bone Miner. Res., 1992, 7:335-343).

European Patent Application Publication Number 525629 (corresponds toCanadian Patent Application Publication Number 2,074,685) disclosescompounds having the general formula: ##STR1##

Copending, commonly assigned U.S. patent application Ser. No. 08/337,920filed Nov. 10, 1994 discloses integrin inhibitors of the general formulashown below: ##STR2##

PCT Patent Application WO 94/08577 published Apr. 28, 1994 disclosesfibrinogen antagonists, including the isoxazole-containing compoundbelow: ##STR3##

Several RGD-peptidomimetic compounds have been reported which blockfibrinogen binding and prevent the formation of platelet thrombi.

European Patent Application Publication Number 478363 relates tocompounds having the general formula: ##STR4##

European Patent Application Publication Number 478328 relates tocompounds having the general formula: ##STR5##

PCT Patent Application 9307867 relates to compounds having the generalformula: ##STR6##

European Patent Application Publication Number 512831 relates tocompounds having the general formula: ##STR7##

Copending commonly assigned U.S. patent application U.S. Ser. No.08/455,768) (filed May 31, 1995, Voss et al.) discloses compounds havingthe general formula: ##STR8## which are useful as α_(v) β₃ antagonists.

None of the above references teaches or suggests the compounds of thepresent invention which are described in detail below.

SUMMARY OF THE INVENTION

The present invention provides novel nonpeptide compounds which bind tointegrin receptors thereby altering cell-matrix and cell-cell adhesionprocesses. The compounds of the present invention are useful for thetreatment of angiogenic disorders, inflammation, bone degradation,tumors, metastases, thrombosis, and other cell aggregation-relatedconditions in a mammal.

One aspect of this invention provides novel compounds of Formula I(described below) which are useful as antagonists of the α_(v) /β₃ orvitronectin receptor. The compounds of the present invention inhibit thebinding of vironectin to α_(v) /β₃ and inhibit cell adhesion. Thepresent invention also includes pharmaceutical compositions containingsuch compounds of Formula I, and methods of using such compounds for theinhibition of angiogenesis, and/or for the treatment of angiogenicdisorders.

The present invention also provides novel compounds, pharmaceuticalcompositions and methods which may be used in the treatment orprevention of diseases which involve cell adhesion processes, including,but not limited to, rheumatoid arthritis, asthma, allergies, adultrespiratory distress syndrome, graft versus host disease, organtransplantation, septic shock, psoriasis, eczema, contact dermatitis,osteoporosis, osteoarthritis, atherosclerosis, metastasis, woundhealing, diabetic retinopathy, ocular vasculopathies, thrombosis,inflammatory bowel disease and other autoimmune diseases.

Also included in the present invention are pharmaceutical kitscomprising one or more containers containing pharmaceutical dosage unitscomprising a compound of Formula I, for the treatment of cell adhesionrelated disorders, including, but not limited to, angiogenic disorders.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel compounds of the Formula I: ##STR9##including their enantiomeric, diastereomeric, pharmaceuticallyacceptable salt or prodrug forms thereof wherein:

R¹ is: ##STR10## A and B are independently CH₂, O or --N(R¹²)--; A¹ andB¹ are independently CH₂ or --N(R¹⁰)--;

D is NH, O, or S;

E-F is --C(R²)═C(R³)--, --N═C(R²)--, --C(R²)═N--, --N═N--, or--CH(R²)CH(R³)--;

G is selected from O or S;

R² and R³ are independently selected from: H, C₁ -C₄ alkoxy, NR¹¹ R¹²,═NR¹², halogen, NO₂, CN, CF₃, C₁ -C₆ alkyl, C₃ -C₆ alkenyl, C₃ -C₇cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, C₂-C₇ alkylcarbonyl, or C₇ -C₁₁ arylcarbonyl;

alternatively, R² and R³ can be taken together to be a 5-7 memberedcarbocyclic or 5-7 membered heterocyclic ring system, said carbocyclicor heterocyclic ring being substituted with 0-2 R⁷ ;

U is selected from:

--(CH₂)_(n) --,

--(CH₂)_(n) N(R¹²) (CH₂)_(m) --,

--(CH₂)_(n) NHNH (CH₂)_(m) --,

--N(R¹⁰)C(═O)--, or

--C (═O)N(R¹⁰)--;

V is selected from:

--(CH₂)_(n) --,

--(C₁ -C₆ alkylene)--Q--, substituted with 0-3 groups independentlyselected from R¹³,

--(C₂ -C₇ alkenylene)--Q--, substituted with 0-3 groups independentlyselected from R¹³,

--(C₂ -C₇ alkynylene)--Q--, substituted with 0-3 groups independentlyselected from R¹³,

--(phenyl)--Q--, said phenyl substituted with 0-2 groups independentlyselected from R¹³,

--(piperidinyl)--Q--, said piperidinyl substituted with 0-2 groupsindependently selected from R¹³,

--(pyridyl)--Q--, said pyridyl substituted with 0-2 groups independentlyselected from R¹³, or

--(pyridazinyl)--Q--, said pyridazinyl substituted with 0-2 groupsindependently selected from R¹³ or R⁷ ;

Q is selected from:

--(CH₂)_(n) --,

--(CH₂)_(n) O(CH₂)_(m) --,

--(CH₂)_(n) N(R¹²)(CH₂)_(m) --,

--N(R¹⁰)C(═O)--, or

--C(═O)N(R¹⁰)--;

W is selected from:

--(CH₂)_(q) C(═O)N(R¹⁰)--, --SCH₂ C(═O)N(R¹⁰)--, or

--C(═O)--N (R¹⁰)--(CH₂)_(q) --;

X is selected from:

--(CH₂)_(q) --CH(R⁸)--CH(R⁹)--, --(CH₂)_(q) --CH(CH₂ R⁹)-- or --CH₂ --

R⁵ is selected from: H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃-C₇ cycloalkyl, C₇ -C₁₄ bicycloalkyl, hydroxy, C₁ -C₆ alkoxy, C₁ -C₆alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, nitro, C₁ -C₆alkylcarbonyl, C₆ -C₁₀ aryl, --N(R¹¹)R¹² ; halo, CF₃, CN, C₁ -C₆alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl;

R⁶ is selected from:

H, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ alkoxy, nitro, C₁ -C₆ alkylcarbonyl,--N(R¹¹)R¹², cyano, halo, --S(O)mR¹⁰, CO₂ R¹⁰, OR¹⁰,

C₆ to C₁₀ aryl optionally substituted with 1-3 groups selected fromhalogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ;

methylenedioxy when R⁶ is a substituent on aryl, or

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl,thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl,indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl,piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl, carbazolyl,pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl, or morpholinyl;

R⁷ is selected from:

H, C₁ -C₁₀ alkyl, hydroxy, C₁ -C₁₀ alkoxy, nitro, C₁ -C₁₀ alkylcarbonyl,--N(R¹¹)R¹², cyano, halo, CO₂ R¹⁰, OR¹⁰ ;

R⁸ is selected from:

CONR¹⁰ R¹¹, --CO₂ R¹⁰,

C₁ -C₁₀ alkyl, substituted with 0-3 R⁶,

C₂ -C₁₀ alkenyl, substituted with 0-3 R⁶,

C₂ -C₁₀ alkynyl, substituted with 0-3 R⁶,

C₃ -C₈ cycloalkyl, substituted with 0-3 R⁶,

C₅ -C₆ cycloalkenyl, substituted with 0-3 R⁶,

aryl, substituted with 0-3 R⁶,

a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl,thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl,indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl,piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl, carbazolyl,pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl or morpholinyl;

R⁹ is selected from: H, hydroxy, C₁ -C₁₀ alkoxy, nitro, N(R¹⁰)R¹⁰,--N(R¹⁶)R¹⁷, C₁ -C₁₀ alkyl substituted with 0-3 R⁶, aryl substitutedwith 0-3 R⁶, heteroaryl substituted with 0-3 R⁶ or C₁ -C₁₀alkylcarbonyl;

R¹⁰ is selected from H or C₁ -C₁₀ alkyl substituted with 0-2 R⁵ ;

R¹¹ is selected from hydrogen, hydroxy, C₁ to C₈ alkyl, C₃ -C₆ alkenyl,C₃ to C₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₁ -C₆ alkoxy,benzyloxy, C₆ to C₁₀ aryl, heteroaryl, heteroarylalkyl, C₇ to C₁₁arylalkyl, adamantylmethyl, or C₁ -C₁₀ alkyl substituted with 0-2 R⁵ ;

alternatively, R¹⁰ and R¹¹ when both are substituents on the samenitrogen atom (as in --NR¹⁰ R¹¹) can be taken together with the nitrogenatom to which they are attached to form a heterocycle selected from:3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl; saidheterocycle being optionally substituted with 1-3 groups selected from:C₁ -C₆ alkyl, C₆ -C₁₀ aryl, heteroaryl, C₇ -C₁₁ arylalkyl, C₁ -C₆alkylcarbonyl, C₃ -C₇ cycloalkylcarbonyl, C₁ -C₆ alkoxycarbonyl, C₇ -C₁₁arylalkoxycarbonyl, C₁ -C₆ alkylsulfonyl or C₆ -C₁₀ arylsulfonyl;

R¹² is selected from:

H, C₁ -C₆ alkyl, C₁ -C₄ alkoxycarbonyl, C₁ -C₆ alkylcarbonyl, C₁ -C₆alkylsulfonyl, aryl(C₁ -C₄ alkyl)sulfonyl, arylsulfonyl, aryl,heteroarylcarbonyl, or heteroarylalkylcarbonyl, wherein said aryl groupsare substituted with 0-3 substituents selected from the group consistingof: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ;

R¹³ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl,C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀ alkoxycarbonyl, CO₂ R¹⁰ or--C(═O)N(R¹⁰)R¹¹ ;

R¹⁶ is selected from:

--C(═O)--O--R^(18a),

--C(═O)--R^(18b),

--SO₂ --R^(18a),

--SO₂ --N(18^(b))₂ ;

R¹⁷ is selected from H or C₁ -C₄ alkyl;

R^(18a) is selected from:

C₁ -C₈ alkyl substituted with 0-2 R¹⁹,

C₂ -C₈ alkenyl substituted with 0-2 R¹⁹,

C₂ -C₈ alkynyl substituted with 0-2 R¹⁹,

C₃ -C₈ cycloalkyl substituted with 0-2 R¹⁹,

aryl substituted with 0-4 R¹⁹,

aryl(C₁ -C₆ alkyl)- substituted with 0-4 R¹⁹,

a heterocyclic ring system selected from

pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl,imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl,isoxazolinyl, isoxazolyl, benzimidazolyl, piperidinyl,tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl,pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclicring being substituted with 0-4 R¹⁹ ;

C₁ -C₆ alkyl substituted with a heterocyclic ring system selected frompyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,isoxazolinyl, isoxazolyl, benzofuranyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl,pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl,indolinyl, or morpholinyl, said heterocyclic ring being substituted with0-4 R¹⁹ ;

R^(18b) is selected from R^(18a) or H;

R¹⁹ is selected from: H, halogen, CF₃, CN, NO₂, NR¹¹ R¹², C₁ -C₈ alkyl,C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁cycloalkylalkyl, aryl, aryl(C₁ -C₆ alkyl)--, C₁ -C₆ alkoxy, or C₁ -C₄alkoxycarbonyl;

R²⁰ is selected from:

hydroxy;

C₁ to C₁₀ alkoxy;

methylcarbonyloxymethoxy-,

ethylcarbonyloxymethoxy-,

t-butylcarbonyloxymethoxy-,

cyclohexylcarbonyloxymethoxy-,

1-(methylcarbonyloxy)ethoxy-,

1-(ethylcarbonyloxy)ethoxy-,

1-(t-butylcarbonyloxy)ethoxy-,

1-(cyclohexylcarbonyloxy)ethoxy-,

i-propyloxycarbonyloxymethoxy-,

t-butyloxycarbonyloxymethoxy-,

1-(i-propyloxycarbonyloxy)ethoxy-,

1-(cyclohexyloxycarbonyloxy)ethoxy-,

1-(t-butyloxycarbonyloxy)ethoxy-,

dimethylaminoethoxy-,

diethylaminoethoxy-,

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl) methoxy-,

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-,

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-,

R²¹ is selected from C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁, cycloalkyl,C₄ -C₁₁ cycloalkylmethyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀alkyl substituted with 0-2 R⁵ ;

m is 0-2;

n is 0-2;

p is 0-2;

q is 0-1; and

r is 0-2;

with the following provisos:

(1) n, m and q are chosen such that the number of atoms connecting R¹and Y is in the range of 8-14; and

(2) when V is -(phenyl)--Q--, then either: U is not a direct bond (i.e.,U is not --(CH₂)_(n) -- where n=0) or Q is not a direct bond (i.e., Q isnot --(CH₂)_(n) -- where n=0).

A preferred embodiment of the invention are compounds of formula (I) asdefined above wherein

R¹ ##STR11## V is selected from: --(CH₂)_(n) --,

--(C₁ -C₆ alkylene)--Q--, substituted with 0-3 groups independentlyselected from R¹³,

--(C₂ -C₇ alkenylene)--Q--, substituted with 0-3 groups independentlyselected from R¹³,

--(C₂ -C₇ alkynylene)--Q--, substituted with 0-3 groups independentlyselected from R¹³,

--(phenyl)--Q--, said phenyl substituted with 0-2 groups independentlyselected from R¹³,

--(pyridyl)--Q--, said pyridyl substituted with 0-2 groups independentlyselected from R¹³, or

--(pyridazinyl)--Q--, said pyridazinyl substituted with 0-2 groupsindependently selected from R¹³ or R⁷ ;

The most preferred compounds of the invention are:

2(S)-Phenylsulfonylamino-3-[2-[2-[3-[(N-imidazolin-2-yl)amino]propyl]-1,3,4-thiadiazol-5-yl]acetyl]aminopropionicacid

2(S)-(3-methylphenylsulfonyl)amino-3-[2-[2-[3-[(N-imidazolin-2-yl)amino]propyl]-1,3,4-thiadiazol-5-yl]acetyl]aminopropionicacid

2(S)-Benzyloxycarbonylamino-3-[[2-[4-[N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

2(S)-(2,4,6-Trimethylphenylsulfonyl)amino-3-[[2-[4-[N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

2(S)-(1-Naphthalenesulfonyl)amino-3-[[2-[4-[N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

2(S)-Benzyloxycarbonylamino-3-[[2-[4-[(N-imidazolin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

2(S)-(2,4,6-Trimethylphenylsulfonyl)amino-3-[[2-[4-[(N-imidazolin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

2(S)-(1-Naphthalenesulfonyl)amino-3-[[2-[4-[(N-imidazolin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

In the present invention it has been discovered that the compounds ofFormula I above are useful as inhibitors of cell-matrix and cell-celladhesion processes. The present invention includes novel compounds ofFormula I and methods for using such compounds for the prevention ortreatment of diseases resulting from abnormal cell adhesion to theextracellular matrix which comprises administering to a host in need ofsuch treatment a therapeutically effective amount of such compound ofFormula I. In the present invention it has also been discovered that thecompounds of Formula I above are useful as inhibitors of α_(v) β₃. Thecompounds of the present invention inhibit the binding of vitronectin toα_(v) β₃ and inhibit cell adhesion.

The present invention also provides pharmaceutical compositionscomprising a compound of Formula I and a pharmaceutically acceptablecarrier.

The compounds of Formula I of the present invention are useful for thetreatment (including prevention) of angiogenic disorders. The term"angiogenic disorders" as used herein includes conditions involvingabnormal neovascularization, such as tumor metastasis and ocularneovascularization, including, for example, diabetic retinopathy,neovascular glaucoma, age-related macular degeneration, and retinal veinocclusion, comprising administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of Formula Idescribed above.

The compounds of Formula I of the present invention may be useful forthe treatment or prevention of other diseases which involve celladhesion processes, including, but not limited to, inflammation, bonedegradation, thromboembolic disorders, restenosis, rheumatoid arthritis,asthma, allergies, adult respiratory distress syndrome, graft versushost disease, organ transplantation rejection, septic shock, psoriasis,eczema, contact dermatitis, osteoporosis, osteoarthritis,atherosclerosis, inflammatory bowel disease and other autoimmunediseases. The compounds of Formula I of the present invention may alsobe useful for wound healing.

The term "thromboembolic disorders" as used herein includes conditionsinvolving platelet activation and aggregation, such as arterial orvenous cardiovascular or cerebrovascular thromboembolic disorders,including, for example, thrombosis, unstable angina, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary and cerebral arterialthrombosis, myocardial infarction, cerebral embolism, kidney embolisms,pulmonary embolisms, or such disorders associated with diabetes,comprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound of Formula I describedabove.

The compounds of the present invention may be used for other ex vivoapplications to prevent cellular adhesion in biological samples.

Other applications of these compounds include prevention of plateletthrombosis, thromboembolism, and reocclusion during and afterthrombolytic therapy and prevention of platelet thrombosis,thromboembolism and reocclusion after angioplasty of coronary and otherarteries and after coronary artery bypass procedures. The compounds ofthe present invention may also be used to prevent myocardial infarction.The compounds of the present invention are useful as thrombolytics forthe treatment of thromboembolic disorders.

The compounds of the present invention can also be administered incombination with one or more additional therapeutic agents select from:anti-coagulant or coagulation inhibitory agents, such as heparin orwarfarin; anti-platelet or platelet inhibitory agents, such as aspirin,piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides,hirudin or argatroban; or thrombolytic or fibrinolytic agents, such asplasminogen activators, anistreplase, urokinase, or streptokinase.

The compounds of Formula I of the present invention can be administeredin combination with one or more of the foregoing additional therapeuticagents, thereby to reduce the doses of each drug required to achieve thedesired therapeutic effect. Thus, the combination treatment of thepresent invention permits the use of lower doses of each component, withreduced adverse, toxic effects of each component. A lower dosageminimizes the potential of side effects of the compounds, therebyproviding an increased margin of safety relative to the margin of safetyfor each component when used as a single agent. Such combinationtherapies may be employed to achieve synergistic or additive therapeuticeffects for the treatment of thromboembolic disorders.

By "therapeutically effective amount" it is meant an amount of acompound of Formula I that when administered alone or in combinationwith an additional therapeutic agent to a cell or mammal is effective toprevent or ameliorate the thromboembolic disease condition or theprogression of the disease.

By "administered in combination" or "combination therapy" it is meantthat the compound of Formula I and one or more additional therapeuticagents are administered concurrently to the mammal being treated. Whenadministered in combination each component may be administered at thesame time or sequentially in any order at different points in time.Thus, each component may be administered separately but sufficientlyclosely in time so as to provide the desired therapeutic effect.

The term anti-coagulant agents (or coagulation inhibitory agents), asused herein, denotes agents that inhibit blood coagulation. Such agentsinclude warfarin (available as Coumadin™) and heparin.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function such as byinhibiting the aggregation, adhesion or granular secretion of platelets.Such agents include the various known non-steroidal anti-inflammatorydrugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac,indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, andpiroxicam, including pharmaceutically acceptable salts or prodrugsthereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), andpiroxicam. Piroxicam is commercially available from Pfizer Inc. (NewYork, N.Y.), as Feldane™. Other suitable anti-platelet agents includeticlopidine, including pharmaceutically acceptable salts or prodrugsthereof. Ticlopidine is also a preferred compound since it is known tobe gentle on the gastro-intestinal tract in use. Still other suitableplatelet inhibitory agents include thromboxane-A2-receptor antagonistsand thromboxane-A2-synthetase inhibitors, as well as pharmaceuticallyacceptable salts or prodrugs thereof.

The phrase thrombin inhibitors (or anti-thrombin agents), as usedherein, denotes inhibitors of the serine protease thrombin and otherinhibitors of thrombin synthesis such as Factor XA. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the granular secretion of plasminogen activator inhibitor-1and/or serotonin) and/or fibrin formation are disrupted. Such inhibitorsinclude boroarginine derivatives and boropeptides, hirudin andargatroban, including pharmaceutically acceptable salts and prodrugsthereof. Boroarginine derivatives and boropeptides include N-acetyl andpeptide derivatives of boronic acid, such as C-terminal α-aminoboronicacid derivatives of lysine, ornithine, arginine, homoarginine andcorresponding isothiouronium analogs thereof. The term hirudin, as usedherein, includes suitable derivatives or analogs of hirudin, referred toherein as hirulogs, such as disulfatohirudin. Boropeptide thrombininhibitors include compounds described in Kettner et al., U.S. Pat. No.5,187,157 and European Patent Application Publication Number 293 881 A2,the disclosures of which are hereby incorporated herein by reference.Other suitable boroarginine derivatives and boropeptide thrombininhibitors include those disclosed in PCT Application Publication Number92/07869 and European Patent Application Publication Number 471 651 A2,the disclosures of which are hereby incorporated herein by reference, intheir entirety.

The phrase thrombolytics (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator,anistreplase, urokinase or streptokinase, including pharmaceuticallyacceptable salts or prodrugs thereof. Tissue plasminogen activator (tPA)is commercially available from Genentech Inc., South San Francisco,Calif. The term anistreplase, as used herein, refers to anisoylatedplasminogen streptokinase activator complex, as described, for example,in European Patent Application No. 028,489, the disclosures of which arehereby incorporated herein by reference herein, in their entirety.Anistreplase is commercially available as Eminase™. The term urokinase,as used herein, is intended to denote both dual and single chainurokinase, the latter also being referred to herein as prourokinase.

Administration of the compounds of Formula I of the invention incombination with such additional therapeutic agent, may afford anefficacy advantage over the compounds and agents alone, and may do sowhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the binding of nitronection or fibrinogen toα_(v) β₃. Such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving α_(v) β₃. Thecompounds of the present invention may also be used in diagnostic assaysinvolving α_(v) β₃.

The compounds herein described may have asymmetric centers. Unlessotherwise indicated, all chiral, diastereomeric and racemic forms areincluded in the present invention. Many geometric isomers of olefins,C═N double bonds, and the like can also be present in the compoundsdescribed herein, and all such stable isomers are contemplated in thepresent invention. It will be appreciated that compounds of the presentinvention that contain asymmetrically substituted carbon atoms may beisolated in optically active or racemic forms. It is well known in theart how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis, from optically active starting materials.All chiral, diastereomeric, racemic forms and all geometric isomericforms of a structure are intended, unless the specific stereochemistryor isomer form is specifically indicated.

When any variable (for example but not limited to, R², R⁴, R⁶, R⁷, R⁸,R¹², and R¹⁴, n, etc.) occurs more than one time in any constituent orin any formula, its definition on each occurrence is independent of itsdefinition at every other occurrence. Thus, for example, if a group isshown to be substituted with 0-2 R⁴, then said group may optionally besubstituted with up to two R⁴ and R⁴ at each occurrence is selectedindependently from the defined list of possible R⁴. Also, by way ofexample, for the group --N(R^(5a))₂, each of the two R^(5a) substituentson N is independently selected from the defined list of possible R^(5a).Similarly, by way of example, for the group --C(R⁷)₂ --, each of the twoR⁷ substituents on C is independently selected from the defined list ofpossible R⁷.

When a bond to a substituent is shown to cross the bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a bond joining a substituent to another group is notspecifically shown or the atom in such other group to which the bondjoins is not specifically shown, then such substituent may form a bondwith any atom on such other group.

When a substituent is listed without indicating the atom via which suchsubstituent is bonded to the rest of the compound of Formula I, thensuch substituent may be bonded via any atom in such substituent. Forexample, when the substituent is piperazinyl or piperidinyl unlessspecified otherwise, said piperazinyl or piperidinyl group may be bondedto the rest of the compound of Formula I via any atom in suchpiperazinyl or piperidinyl group.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. By stable compound orstable structure it is meant herein a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture, and formulation into an efficacious therapeutic agent.

The term "substituted", as used herein, means that any one or morehydrogen on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

As used herein, "alkyl" is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms (for example, "C₁ -C₁₀ " denotes alkylhaving 1 to 10 carbon atoms); "alkoxy" represents an alkyl group ofindicated number of carbon atoms attached through an oxygen bridge;"cycloalkyl" is intended to include saturated ring groups, includingmono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, andcyclobutyl; cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl; and"bicycloalkyl" is intended to include saturated bicyclic ring groupssuch as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended toinclude hydrocarbon chains of either a straight or branchedconfiguration and one or more unsaturated carbon-carbon bonds which mayoccur in any stable point along the chain, such as ethenyl, propenyl andthe like; and "alkynyl" is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or more triplecarbon-carbon bonds which may occur in any stable point along the chain,such as ethynyl, propynyl and the like.

The terms "alkylene", "alkenylene", "phenylene", and the like, refer toalkyl, alkenyl, and phenyl groups, respectively, which are connected bytwo bonds to the rest of the structure of Formula I. Such "alkylene","alkenylene", "phenylene", and the like, may alternatively andequivalently be denoted herein as "-(alkyl)-", "-(alkenyl)-" and"-(phenyl)-", and the like.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo andiodo; and "counterion" is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate and thelike.

As used herein, "aryl" or "aromatic residue" is intended to mean phenylor naphthyl optionally substituted with 0-3 groups independentlyselected from methyl, methoxy, amino, hydroxy, halogen, C₁ -C₆ alkoxy,C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl,methylenedioxydiyl, ethylenedioxydiyl; the term "arylalkyl" representsan aryl group attached through an alkyl bridge.

As used herein, "carbocycle" or "carbocyclic residue" is intended tomean any stable 3- to 7-membered monocyclic or bicyclic or 7- to14-membered bicyclic or tricyclic or an up to 26-membered polycycliccarbon ring, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocyles include, but are not limited to,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl,indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" or "heterocyclic" is intended tomean a stable 5- to 7-membered monocyclic or bicyclic or 7- to10-membered bicyclic heterocyclic ring which may be saturated, partiallyunsaturated, or aromatic, and which consists of carbon atoms and from 1to 4 heteroatoms independently selected from the group consisting of N,O and S and wherein the nitrogen and sulfur heteroatoms may optionallybe oxidized, and the nitrogen may optionally be quaternized, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic ring maybe attached to its pendant group at any heteroatom or carbon atom whichresults in a stable structure. The heterocyclic rings described hereinmay be substituted on carbon or on a nitrogen atom if the resultingcompound is stable. Examples of such heterocycles include, but are notlimited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl),thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl,quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl,pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl oroctahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl,chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl,pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole,β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl,isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl,morpholinyl or oxazolidinyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term "heteroaryl" refers to aromatic heterocyclicgroups. Such heteroaryl groups are preferably 5-6 membered monocylicgroups or 8-10 membered fused bicyclic groups. Examples of suchheteroaryl groups include, but are not limited to pyridyl (pyridinyl),pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl,benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, orisoquinolinyl.

As used herein, the term "chiral amine" refers to any amine containingcompound that also contains a chiral center. Such compounds include, byway of example and without limitation, either enantiomer ofcinchonidine, ephedrine, 2-phenylglycinol, 2-amino-3-methoxy-1-propanol,quinidine and pseudoephedrine.

As used herein, "pharmaceutically acceptable salts" refer to derivativesof the disclosed compounds wherein the parent compound of Formula I ismodified by making acid or base salts of the compound of Formula I.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like.

"Prodrugs" are considered to be any covalently bonded carriers whichrelease the active parent drug according to Formula I in vivo when suchprodrug is administered to a mammalian subject. Prodrugs of thecompounds of Formula I are prepared by modifying functional groupspresent in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds of Formula I wherein hydroxyl,amino, sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofFormula I, and the like. Examples of the prodrug forms of the compoundsof the present invention include the following esters:

methyl, ethyl, isopropyl,

methylcarbonyloxymethyl-, ethylcarbonyloxymethyl-,

t-butylcarbonyloxymethyl-,

cyclohexylcarbonyloxymethyl-,

1-(methylcarbonyloxy)ethyl-,

1-(ethylcarbonyloxy)ethyl-,

1-(t-butylcarbonyloxy)ethyl-,

1-(cyclohexylcarbonyloxy)ethyl-,

i-propyloxycarbonyloxymethyl-,

cyclohexylcarbonyloxymethyl-,

t-butyloxycarbonyloxymethyl-,

1-(i-propyloxycarbonyloxy)ethyl-,

1-(cyclohexyloxycarbonyloxy)ethyl-,

1-(t-butyloxycarbonyloxy)ethyl-,

dimethylaminoethyl-, diethylaminoethyl-,

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methyl-,

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methyl-,

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methyl-,

1-(2-(2-methoxypropyl)-carbonyloxy)ethyl-.

The pharmaceutically acceptable salts of the compounds of Formula Iinclude the conventional non-toxic salts or the quaternary ammoniumsalts of the compounds of Formula I formed, for example, from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; andthe salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the compounds of Formula I which contain a basic oracidic moiety by conventional chemical methods. Generally, the salts areprepared by reacting the free base or acid with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidor base in a suitable solvent or various combinations of solvents.

The pharmaceutically acceptable salts of the acids of Formula I with anappropriate amount of a base, such as an alkali or alkaline earth metalhydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or anorganic base such as an amine, e.g., dibenzylethylenediamine,trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or aquaternary ammonium hydroxide such as tetramethylammoinum hydroxide andthe like.

As discussed above, pharmaceutically acceptable salts of the compoundsof the invention can be prepared by reacting the free acid or base formsof these compounds with a stoichiometric amount of the appropriate baseor acid, respectively, in water or in an organic solvent, or in amixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosureof which is hereby incorporated by reference.

The disclosures of all of the references cited herein are herebyincorporated herein by reference in their entirety.

SYNTHESIS

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The following abbreviations are used herein:

    ______________________________________                                        Boc          tert-butyloxycarbonyl                                            Boc.sub.2 O  di-tert-butyl dicarbonate                                        Cbz          benzyloxycarbonyl                                                DEC          1-(3-dimethylaminopropyl)-3-                                                  ethylcarbodiimide hydrochloride                                  DIEA         diisopropylethylamine                                            DMAP         4-dimethylaminopyridine                                          DMF          N,N-dimethylformamide                                            EtOAc        ethyl acetate                                                    EtOH         ethyl alcohol                                                    PLE          Pig liver esterase                                               pyr          pyridine                                                         TBTU         2-(1H-Benzotriazol-1-yl)-1,1,3,3-                                             tetramethyluronium tetrafluoroborate                             TFA          trifluoroacetic acid                                             THF          tetrahydrofuran                                                  ______________________________________                                    

Compounds of Formula I wherein the central heterocycle is a1,3,4-thiadiazole ring can be conveniently prepared by cyclization ofN,N'-diacylhydrazine in the presence of Lawessen reagent(M. P. Cava, etal, Tetrahedron Lett. 1985, 41, 5061) or P₂ S₅ (stelle, et al, J. Prakt.Chem 1904, 69, 145).

Scheme I illustrates one synthetic sequence which will provide the1,3,4-thiadiazoles of this invention. An appropriately substituted esteris treated with hydrazine monohydrate to afford the hydrazide which isthen converted to N,N'-diacylhydrazine on reaction with an acid chloridein aqueous THF using NaHCO3 as base. The N,N'-diacylhydrazine thusobtained is then cyclized to afford the 1,3,4-thiadiazole.

Subsequent hydrolysis of the ester using conventional methods known toone skilled in the art of organic synthesis gives the desired acid.Coupling of the resulting acid to appropriately substituted α- orβ-amino esters affords an intermediate which can be deprotected to givecompounds of Formula I. The coupling is carried out using any of themany methods for the formation of amide bonds known to one skilled inthe art of organic synthesis. These methods include but are not limitedto conversion of the acid to the corresponding acid chloride, or use ofstandard coupling procedures such as the azide method, mixed carbonicacid anhydride (isobutyl chloroformate) method, carbodiimide(dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-solublecarbodiimides) method, active ester (p-nitrophenyl ester,N-hydroxysuccinic imido ester) method, carbonyldiimidazole method,phosphorus reagents such as BOP-Cl. Some of these methods (especiallythe carbodiimide) can be enhanced by the addition of1-hydroxybenzotriazole. ##STR12##

Alternately, as depicted in Scheme Ia and Ib, the above sequence can becarried out on an ester bearing a suitable functional group or protectedfunctional group which can be converted into R¹ at a suitable stage ofthe synthesis of the target molecules. ##STR13##

Additional 1,3,4-thiadiazolyl acids useful as starting materials for thepreparation of compounds of Formula I, wherein W is --SCH₂ C(═O)N(R¹⁰)--can be prepared by substitution of a suitably substituted1,3,4-thiadiazolyl sulfone with an acid thiol as shown in Scheme Icusing literature methods or modifications thereof. (Fujii et al, J.Pharm. Soc. Japan 1954, 74, 1056; Young et al, J. Am. Chem. Soc. 1955,77, 400). ##STR14##

The appropriately substituted racemic b-amino acids may be purchasedcommercially or, as is shown in Scheme II, Method 1, prepared from theappropriate aldehyde, malonic acid and ammonium acetate according to theprocedure of Johnson and Livak (J. Am. Chem. Soc. 1936, 58, 299).Racemic b-substituted-b-amino esters may be prepared through thereaction of dialkylcuprates or alkyllithiums with4-benzoyloxy-2-azetidinone followed by treatment with anhydrous ethanol(Scheme I, Method 2) or by reductive amination of b-keto esters as isdescribed in WO9316038. (Also see Rico et al., J. Org. Chem. 1993, 58,7948-51.) Enantiomerically pure b-substituted-b-amino acids can beobtained through the optical resolution of the racemic mixture or can beprepared using numerous methods, including: Arndt-Eistert homologationof the corresponding a-amino acids as shown in Scheme II, Method 3 (seeMeier, and Zeller, Angew, Chem. Int. Ed. Engl. 1975, 14, 32; Rodriguez,et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985,28, 434 and references cited within); and through an enantioselectivehydrogenation of a dehydroamino acid as is shown in Scheme II, Method 4(see Asymmetric Synthesis, Vol. 5, (Morrison, ed.) Academic Press, NewYork, 1985). A comprehensive treatise on the preparation of b-amino acidderivatives may be found in patent application WO 9307867, thedisclosure of which is hereby incorporated by reference. ##STR15##

The synthesis of N² -substituted diaminopropionic acid derivatives canbe carried out via Hoffman rearrangement of a wide variety of asparaginederivatives as described in Synthesis, 266-267, (1981).

Synthesis of compounds of Formula I wherein the central heterocycle is a1,3,4-oxadiazole ring, e.g. G═O, is shown in Scheme III. Cyclization ofan appropriately substituted N,N'-diacylhydrazine in the presence ofPOCl₃ according to the method of Klingsberg (J. Am. Chem. Soc. 1958, 80,5788) gives the intermediate 1,3,4-oxadiazolyl ester. This ester can beconverted to compounds of Formula I using the methods described herein.##STR16##

Alternately, the 1,3,4-oxadiazoles may be prepared from an ester bearingan appropriate functional group such as nitro or vinyl group which canbe converted into R¹ at an appropriate stage of the synthesis of thetarget molecules.

Componds of formula I wherein G═O and W is --SCH₂ C(═O)N(R¹⁰)-- may beprepared from an appropriately substituted acylhydrazine adopting themethod described by Confalone (J. Am. Che. Soc. 1983, 105, 902), asdepicted in Scheme IV. ##STR17##

The detailed processes for preparing the compounds of Formula I areillustrated by the following Examples. It is, however, understood thatthis invention is not limited to the specific details of these examples.Melting points are uncorrected. Proton nuclear magnetic resonancespectra (¹ H NMR) were measured in chloroform-d (CDCl₃) unless otherwisespecified and the peaks are reported in parts per million (ppm)downfield from tetramethylsilane (TMS). The coupling patterns arereported as follows: s, singlet; d, doublet; t, triplet; q, quartet; qt,quintet; m, multiplet.

EXAMPLE 432(S)-Phenylsulfonylamino-3-[2-[2-[3-[(N-imidazolin-2-yl)amino]propyl]-1,3,4-thiadiazol-5-yl]acetyl]aminopropionicacid

Part A. 4-nitrobutyrylhydrazine

Methyl 4-nitrobutyrate (5.5 g, 37.5 mmol) and hydrazine monohydrate(1.88 g, 37.5 mmol) were mixed in methanol (30ml). The resultingsolution was stirred at rt for 50 hrs, and then evaporated under reducedpressure. The oily residue was pure enough for next reaction. ¹ HNMR(300 MHz)δ2.08(qt, 2H), 2.20(t, 2H), 4.50(t, 2H); MS(HH₃ -CI) Calc.for (M+1)⁺ :148. Found: 148.

Part B.N-(4--Nitrobutyryl)--N'(methoxycarbonylacetyl)hydrazine

To a suspesion of 4-nitrobutyrylhydrazine (5.5 g, 37.5 mmol) in aqueousTHF (80 ml, 1:1 v/v) containing sodium bicarbonate (4.1 g, 48.8 mmol),cooled with ice-water, was added methyl malonyl chloride (6.1 g, 44.8mmol) dropwise. After addition, the ice-water bath was removed and themixture was stirred at rt for 2 hrs. The THF was evaporated underreduced pressure and the product as a solid powder was then collected byfiltration and dried. (7.9 g, 85% yield). ¹ H NMR(300 MHz) δ2.10(qt,2H), 2.25(t, 2H), 3.34(s, 2H), 3.62(s,3H), 4.79(t, 2H), 10.02(s, 1H),10.10(s, 1H); MS(NH₃ -DCI) Calc. for (M+NH₄)⁺ : 265. Found: 265.

Part C. Methyl 2-[2-(3-nitropropyl)-1,3,4-thiadiazol-5-yl]acetate

A mixture of N-(4-nitrobutyryl)-N'-(methoxycarbonylacetyl)hydrazine (2.0g, 8.1 mmol) and Lawesson's reagent (1.8 g, 4.4 mmol) in anhydrous THF(30 ml) was gently refluxed for 1 hr. The solution was then evaporatedto dryness and the residue was dissolved in ethyl acetate and washedwith saturated NaHCO3, brine, then dried. Evaporation followed bychromatography using a mixture of ethyl acetate and hexane (1:1. v:v) aseluent gave the product as an oil (1.1 g, 56% yield). ¹ H NMR(300 MHz)δ2.60(qt, 2H), 3.24(t, 2H), 3.80(s, 3H), 4.10(s, 2H), 4.60(t, 2H);MS(NH₃ -CI) Calc. for (M+1)⁺ : 246. Found: 246.

Part D. 2-[2-(3-nitropropyl)-1,3,4-thiadiazol-5-yl]acetic acid

Methyl 2-[2-(3-nitropropyl)-1,3,4-thiadiazol-5-yl]acetate (1.05 g, 4.3mmol) was dissolved in aqueous THF (30 ml, 1:1, v:v) containing 450 mg(10.7 mmol) of LiOH.H2O. The solution was stirred at rt for 8 hrs, andthen acidified with 6N HCl to a PH of around 2.0. The solution wasevaporated to dryness and the residue was washed with acetone. Afterremoval of acetone, the product was dried (800 mg, 81% yield). ¹ HNMR(300 MHz, DMSO) δ2.34(qt, 2H), 3.16(t, 2H), 4.18(s, 2H), 4.68(t, 2H);MS(NH₃ -CI) Calc. for (M+1)⁺ : 232. Found: 232.

Part E. Methyl N² -Cbz-L-2,3-diaminopropionate HCl salt

N² -Cbz-L-2,3-diaminopropionic acid (10 mmol, 2.39 g) was dissolved in20 mL methanol and 20 mL 4 N HCl in dioxane and the solution was stirredfor 4 hours and then concentrated to give a solid. The solid was washedwith ether several times to give 2.50 g (87%) product. NMR (DMSO-d₆): d8.38 (b, 3H); 7.96 (d, 1H); 7.38 (m, 5H); 5.05 (s, 2H); 4.44 (m, 1H);3.66 (s, 3H); 3.14 (m, 2H).

Part F: Methyl N² -Cbz--N³ -Boc-L-2,3-diaminopropionate

To a solution of methyl N² -Cbz-(S)-2,3-diaminopropionate HCl salt (16.3mmol, 4.7 g) and di-tert-butyl dicarbonate (16.3 mmol, 3.56 g) in 30 mLchloroform cooled in an ice bath was added triethylamine (34 mmol, 4.7mL) and the solution was stirred in the ice bath for 1 hour and at roomtemperature for 3 hours and concentrated. The residue was taken up inethyl acetate and the solution was washed with dilute citric acid,brine, NaHCO₃ and brine, dried (MgSO₄), and concentrated.Crystallization from ether/petroleum ether gave 5.2 g (92%) product. NMR(DMSO-d₆): d 7.60 (d, 1H); 7.35 (m, 5H); 6.88 (t, 1H); 5.02 (s, 2H);4.14 (m, 1H); 3.60 (s, 3H); 3.28 (m, 2H); 1.37 (s, 9H).

Part G: Methyl N³ -Boc-(S)-2,3-diaminopropionate Formic acid salt

A mixture of methyl N² -Cbz-N³ -Boc-(S)-2,3-diaminopropionate. (14 mmo,5.0 g), formic acid (42 mmol, 1.6 mL) and 10% Pd/C (500 mg) in 40 mLmethanol was stirred at room temperature for 1 hour and filtered througha celite. The filtrate was concentrated and the residue was trituratedwith ether-petroleum ether to give 3.7 g (100%) solid product. NMR(DMSO-d₆): δ8.20(s, 1H); 6.90 (t, 1H); 5.36 (b, 3H); 3.61 9s, 3H); 3.51(t, 1H); 3.18 (t, 2H); 1.38 (s, 9H).

Part H. Methyl N² -phenylsulfonyl-N³ -Boc-(S)-2,3-diaminopropionate

To a mixture of methyl N³ -Boc-(S)-2,3-diaminopropionate HCO₂ H salt(3.89, 14.7 mmol) and diisoproppylethylamine (3.3 g, 32.3mmol) in CH₂Cl₂ (60 ml), cooled with ice-water, was added phenylsulfonyl chloride(2.86 g, 16.22 mmol). After stirring at rt for 24 hrs, the resultingreaction mixture was diluted with ethyl acetate(150 ml), washed withdilute citric acid, saturated NaHCO₃ and brine, and then dried.Concentration afforded the product as a foam(5.0 g, 95% yield). ¹ HNMR(300 MHz)δ1.52(s, 9H), 3.46(m, 2H), 3.56(s, 3H), 4.00(m, 1H), 5.00(m,1H), 5.74(d, 1H), 7.56(m, 3H), 7.82(m, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺: 359. Found: 359.

Part I. Methyl N² -phenylsulfonyl-3(S)-2,3-diaminopropionate HCl salt

Methyl N² -phenylsulfonyl-N³ -Boc-(S)-2,3-diaminopropionate (4.5 g, 12.6mmol) was dissolved in dioxane (8 ml) and then 4N HCl in dioxane (8 ml)was added. The resulting solution was stirred at rt for 5 hrs and thenevaporated to give a foam (3.7 g, 100% yield). ¹ H NMR(300 MHz,DMSO-d₆)δ2.78(m, 2H), 3.56(s, 3H), 3.68(m, 1H), 5.70(d, 1H), 7.46(m,3H), 7.68(m, 2H); MS(ESI) Calc. for (M+1)⁺ : 259. Found: 259(free base).

Part J. Methyl2(S)-phenylsulfonyl-3-[2-[2-(3-nitropropyl)-1,3,4-thiadiazol-5-yl]acety]diaminopropionate

To a mixture of 2-[2-(3-nitropropyl)-1,3,4-thiadiazol-5-yl]acetic acid(510 mg, 2.2 mmol), methyl N² -phenylsulfonyl-(S)-2,3-diaminopropionateHCl salt (650 mg, 2.2 mmol) and triethylamine (1.35 ml, 8.8 mmol) in DMF(12 ml), cooled with ice-water, was added TBTU (700 g, 2.2 mmol). Afterstirring for 3 hrs, the reaction mixture was diluted with ethyl acetateand washed with dilute citric acid, dilute NaHCO₃ and brinesuccessively, then dried. Concentration followed by chromatography usinga mixture of ethyl acetate and hexane as the eluent gave the product asan amorphous solid (645 mg, 62% yield). ¹ H NMR(300 MHz)δ2.58 (qt, 2H),3.26(t, 2H), 3.54(m, 3H), 3.58(s, 3H), 3.70(m, 1H), 4.02(m, 1H), 4.08(s,2H), 4.58(t, 2H), 5.76(d, 1H), 7.08(s, 7H), 7.549m, 3H), 7.80(m, 2H);MS(NH₃ -CI) Calc. for (M+1)⁺ : 472. Found: 472.

Part K. Methyl2(S)-phenylsulfonyl-3-[2-[2-(3-aminopropyl)-1,3,4-thiadiazol-5yl]acety]diaminopropionate AcOH salt

Methyl2(S)-phenylsulfonyl-3-[2-[2-(3-nitropropyl)-1,3,4-thiadiazol-5-yl]acetyl]diaminopropionate(400 mg, 0.85 mmol) was dissolved in a mixed solvent of methanol andacetic acid (12 ml, 1:1, v:v) and PtO₂ (40 mg) was added. The resultingmixture was hydrogenated in a shaking bottle for 30 hrs, and then wasfiltered through a short column of Zeliot. The filtrate was concentratedand the residue dried to give an oily product (410 mg, 96% yield). ¹ HNMR(300 MHz, DMSO-d₆)δ2.76(qt, 2H), 3.08(t, 2H), 3.20(t, 2H), 3.34(s,3H), 3.38(m, 2H), 3.90(m, 3H), 7.58(m, 3H), 7.749m, 2H), 8.749s, 1H);MS(NH₃ -CI) Calc. for (M+1)⁺ : 442. Found: 442.

Part L. Methyl2(S)-phenylsulfonyl-3-[2-[2-[3-[(N-imidazolin-2-yl)amino]propyl]-1,3,4-thiadiazol-5-yl]acety]diaminopropionate

A solution of methyl2(S)-phenylsulfonyl-3-[2-[2-(3-nitropropyl)-1,3,4-thiadiazol-5-yl]acetyl]diaminopropionate(425 mg, 0.85 mmol) and 2-methylthio-2-imidazoline hydriode (207 mg,0.85 mmol) in pyridine (10 ml) was heated at 70° C. for 5 hrs. Thesolution was then concentrated and the residue was chromatographed usinga mixture of methylene chloride and methanol as the eluent to afford anoily pruduct (250 mg, 58% yield).¹ H NMR(300 MHz, CD₃ OD)δ2.08(qt, 2H),3.18(t, 2H), 3.30(m, 3H), 3.40(s, 3H), 3.54(dd, 1H), 3.66(s, 4H),4.00(s, 2H)r 4.10(dd, 1H), 7.52(m, 3H), 7.80(m, 2H); MS(ESI) Calc. for(M+1)⁺ : 510. Found: 510.

Part M.2(S)-phenylsulfonyl-3-[2-[2-[3-[(N-imidazolin-2-yl)amino]propyl]-1,3,4-thiadiazol-5-yl]acety]diaminopropionicacid HCl salt

Methyl2(S)-phenylsulfonyl-3-[2-[2-[3-[(N-imidazolin-2-yl)amino]propyl]-1,3,4-thiadiazol-5-yl]acety]diaminopropionate(230 mg, 0.45 mmol) was dissolved in 4N HCl (9 ml) and the solution wasstirred at rt for 40 hrs, then concentrated under reduced pressure todryness to afford the product as an amorphous solid (200 mg, 91% yield).Further puriofication via reverse phase HPLC using a mixture ofacetonitrile and 0.1% TFA in water as the eluent gave the test sample. ¹H NMR(300 MHz, DMSO-D₆)δ1.96(qt, 2H), 3.08(t, 2H), 3.24(m, 3H), 3.40(m,1H), 3.90(m, 3H), 7.56(m, 3H), 7.58(m, 2H), 8.22(d, 1H), 8.46(t, 1H),8.56(t, 1H); MS(ESI) Calc. for (M+1)⁺ : 496. Found: 496.

EXAMPLE 442(S)-(3-methylphenylsulfonyl)amino-3-[2-[2-[3-[(N-imidazolin-2-yl)amino]propyl]-1,3,4-thiadiazol-5-yl]acetyl]aminopropionicacid

Part A. Methyl N² -3-methylphenylsulfonyl-N³-Boc-(S)-2,3-diaminopropionate

To a mixture of methyl N³ -Boc-(S)-2,3-diaminopropionate HCO₂ H salt(3.8 g, 14.7 mmol) and diisoproppylethylamine (3.3 g, 32.3 mmol) in CH₂Cl₂ (60 ml), cooled with ice-water, was added 3-methylsulfonyl chloride(3.1 g, 16.2 mmol). After stirring at rt for 24 hrs, the resultingreaction mixture was diluted with ethyl acetate (150 ml), washed withdilute citric acid, saturated NaHCO₃ and brine, and then dried.Concentration afforded the product as a foam (5.1 g, 95% yield). ¹ HNMR(300 MHz, CDCl₃)δ1.58(s, 9H), 2.30(s, 3H), 2.72(m, 1H), 2.98(m, 1H),4.10(m, 1H), 5,80(s, 1H), 7.40(d, J=5, 2H), 7.50(m, 1H), 7.56(s, 1H),8.40(d, J=6, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 373. Found: 373.

Part B. Methyl N² -3-methylphenylsulfonyl-(S)-2,3-diaminopropionate HClsalt

Methyl N² -3-methylphenylsulfonyl-N³ -Boc-(S)-2,3-diaminopropionate (4.5g, 12.1 mmol) was dissolved in dioxane (8 ml) and then 4N HCl in dioxane(8 ml) was added. The resulting solution was stirred at rt for 5 hrs andthen evaporated to give a foam (3.7 g, 100% yield). ¹ H NMR(300 MHz,DMSO-d₆)δ2.40(s, 3H), 2.86(m, 1H), 3.10(m, 1H), 3.40(s, 3H), 4.28(m,1H), 7.48(d,J=5 2H), 7.60(m, 1H), 7.62(s, 1H) 8.39(s, broad, 2H),8.62(d, J=6, 1H); MS(ESI) Calc. for (M+1)⁺ : 273. Found: 273 (freebase).

Part C. Methyl2(S)-(3-methylphenyl)sulfonylamino-3-[2-[2-(3-nitropropyl)-1,3,4-thiadiazol-5yl]acety]aminopropionate

To a mixture of 2-[2-(3-nitropropyl)-1,3,4-thiadiazol-5-yl]acetic acid(430 mg, 1.86 mmol), methyl N²-3-methylphenylsulfonyl-(S)-2,3-diaminopropionate HCl salt (630 mg, 2.0mmol) and triethylamine (1.1 ml, 8.2 mmol) in DMF (10 ml), cooled withice-water, was added TBTU (660 mg, 2.0 mmol). After stirring for 3 hrs,the reaction mixture was diluted with ethyl acetate and washed withdilute citric acid, dilute NaHCO₃ and brine successively, then dried.Concentration followed by chromatography using a mixture of ethylacetate and hexane as the eluent gave the product as an amorphous solid(360 mg, 40% yield).¹ H NMR(300 MHz)δ2.40(s, 3H), 2.58(qt, 2H), 3.269t,2H), 3.52(s, 3H), 3.62(m, 2H), 4.06(m, 1H), 4.10(s, 2H), 4.59(t, 2H),7.36(m, 2H), 7.60(m, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 486. Found:486.

Part D. Methyl2(S)-(3-methylphenyl)sulfonylamino-3-[2-[2-(3-aminopropyl)-1,3,4-thiadiazol-5-yl]acety]aminopropionateAcOH salt

Methyl2(S)-(3-methylphenyl)sulfonylamino-3-[2-[2-(3-nitropropyl)-1,3,4-thiadiazol-5-yl]acetyl]aminopropionate(140 mg, 0.29 mmol) was dissolved in a mixed solvent of methanol andacetic acid (20 ml, 1:1, v:v) and PtO₂ (30 mg) was added. The resultingmixture was hydrogenated in a shaking bottle for 24 hrs, and then wasfiltered through a short column of Zeliot. The filtrate was concentratedand the residue dried to give an oily product (120 mg, 91% yield). ¹ HNMR(300 MHz, DMSO-d₆)δ1.90(qt, 3H), 2.56(s, 3H), 2.78(t, 2H), 3.10(t,2H), 3.28(s, 3H), 3.36(m, 2H), 3.84(m, 3H), 7.30(m, 2H), 7.42(m, 1H),7.74(d, 1H), 8.58(s, 1H); MS(ESI) Calc. for (M+1)⁺ : 456. Found: 456.

Part E. Methyl2(S)-(3-methylphenyl)sulfonylamino-3-[2-[2-[3-[(N-imidazolin-2-yl)amino]propyl]-1,3,4-thiadiazol-5-yl]acety]aminopropionate

A solution of methyl2(S)-(3-methylphenyl)sulfonylamino-3-[2-[2-(3-nitropropyl)-1,3,4-thiodiazol-5-yl]acetyl]aminopropionate(130 mg, 0.29 mmol) and 2-methylthio-2-imidazoline hydriode (78 mg, 0.32mmol) in pyridine (5 ml) was heated at 70° C. for 5 hrs. The solutionwas then concentrated and the residue was chromatographed using amixture of methylene chloride and methanol as the eluent to afford anoily pruduct (90 mg, 59% yield).¹ H NMR(300 HMz, DMSO-d₆)δ1.90(qt, 3H),2.56(s, 3H), 3.04(t, 2H), 3.20(m, 2H), 3.28(s, 3H), 3.58(m, 2H), 3.56(m,4H), 3.84(m, 3H), 7.30(m, 2H), 7.42(m, 1H), 7.74(d, 1H), 8.24(s, 1H),8.46(s, 1H); MS(ESI) Calc. for (M+1)⁺ : 524. Found: 524.

Part F.2(S)-(3-methylphenyl)sulfonylamino-3-[2-[2-[3-[(N-imidazolin-2-yl)amino]propyl]-1,3,4-thiadiazol-5-yl]acety]aminopropionicacid HCl salt

Methyl2(S)-(3-methylphenyl)sulfonylamino-3-[2-[2-[3-[(N-imidazolin-2-yl)amino]propyl]-1,3,4-thiadiazol-5-yl]acety]aminopropionate(80 mg, 0.15 mmol) was dissolved in 4N HCl (6 ml) and the solution wasstirred at rt for 36 hrs, then concentrated under reduced pressure todryness, affording the product as an amorphous solid (75 mg, 97% yield).Further puriofication via reverse phase HPLC using a mixture ofacetonitrile and 0.1% TFA in water as the eluent gave the test sample. ¹H NMR(300 MHz, DMSO-D₆)δ2.96(qt, 2H), 2.60(s, 3H), 3.08(t, 2H), 3.20(m,3H), 3.40(m, 1H), 3.58(s, 4H), 3.94(m, 3H), 7.30(m, 3H), 7.42(m, 1H),7.58(m, 2H), 8.20(d, 1H), 8.38(t, 1H), 8.50(m, 1H); MS(ESI) Calc. for(M+1)⁺ : 510. Found: 510.

EXAMPLE 1762(S)-Benzyloxycarbonylamino-3-[[2-[4-[N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

Part A. Pent-4-enoyl hydrazide

A mixture of pent-4-enoic acid ethyl ester (12.1 g, 94.5 mmol) andhydrazine monohydrate (4.6 ml, 94.5 mmol) in methanol (75 ml) wasstirred at rt for 48 hrs. The volatile portion of the reaction mixturewas then removed. The product was obtained as an oil (9.5 g, 94% yield).¹ H NMR(300 MHz)δ1.56(m, 2H), 2.30(t, 2H), 5.20(m, 2H), 5.80(m, 1H);MS(NH₃ -CI) Calcd. for (M+1)⁺ : 115. Found: 115

Part B. N-(Pent-4-enoic)-N'-(methoxycarbonylcarbonyl)hydrazine

To a solution of pent-4-enoic hydrazine (10.8 g, 94.5 mmol) in aqueousTHF (80 ml, 1:1, v:v) containing NaHCO₃ (11.9 g, 141.7 mmol) cooled inan ice-water bath was added methyl oxalyl chloride (13.0 ml, 141.7 mmol)dropwise. After addition, the mixture was stirred in the ice-water bathfor additional 30 mins, and then at rt overnight. The THF was removedunder reduced pressure and the aqueous residue was extracted with ethylacetate. The ethyl acetate solution was washed with brine and then driedover Na₂ SO₄. Concentration afforded the product as an oil (12.3 g, 65%yield). ¹ H NMR (300 MHz)δ1.60(qt, 2H), 2.44(t, 2H), 3.96(s, 3H),5.10(m, 2H), 5.80(m, 1H); MS(NH₃ -CI) Calcd. for (M+1)⁺ : 201. Found:201.

Part C. Methyl [2-(but-3-enyl)-1,3,4-thiadiazol-5-yl]carboxylate

N-(Pent-4-enoic)-N'-(methoxycarbonylcarbonyl)hydrazine (2.13 g, 10.6mmol) was dissolved in anhydrous THF (20 ml) and then was heated togentle refluxing. Lawesson reagent (2.15 g, 5.3 mmol) was introduced andstirring was continued under such conditions for 3 hrs. The solvent wasremoved under reduced pressure and the residue was dissloved in ethylacetate, washed with saturated NaHCO₃ and brine, then dried over Na₂SO₄. After removal of ethyl acetate, the residue was chromatographedusing a mixture of ethyl acetate and hexane as the eluent to give theproduct as a white solid (1.5 g, 73% yield). ¹ H NMR(300 MHz)δ2.60(qt,2H), 3.32(t, 2H), 4.06(s, 3H), 5.14(m, 2H), 5.84(m, 1H); MS(NH₃ -CI)Calcd. for (M+1)⁺ : 199. Found: 199.

Part C. Methyl [2-(4-hydroxybutyl)-1,3,4-thiadiazol-5-yl]carboxylate

Methyl [2-(but-3-enyl)-1,3,4-thiadiazol-5-yl]carboxylate (420 mg, 2.13mmol) was dissolved in anhydrous THF (5 ml) and then cooled with anice-water bath to 0° C. 9-BBN (290 mg, 2.34 mmol) dissolved in THF (5ml) was introduced and the resulting reaction mixture was kept stirringat 0° C. for 3 hrs, then at rt for 5 hrs. NaOAc (1 g) dissolved in water(5 ml) was added, followed by introduction of 1 ml of 30% H₂ O₂. Afterstirred further at rt for 2 hrs, the mixture was extracted with ethylacetate. The extract was washed with brine and then dried over Na₂ SO₄.Concentration followed by chromatography using ethyl acetate as theeluent yielded the product as a white powder (420 mg, 92% yield). ¹ HNMR(300 MHz)δ1.64(m, 2H), 1.90(m, 2H), 3.24(t, 2H), 3.76(q, 2H), 3.82(t,1H), 4.06(s, 1H); MS(NH₃ -CI) Calcd. for (M+1)⁺ : 217. Found: 217.

Part D. Methyl [2-(4-oxobutyl)-1,3,4-thiadiazol-5-yl]carboxylate

Methyl [2-(4-hydroxybutyl)-1,3,4-thiadiazol-5-yl]carboxylate (210 mg,0.97 mmol) was dissloved in CH₂ Cl₂, followed by introduction of PCC(314 mg, 1.45 mmol). The mixture was stirred at rt for 5 hrs, and thenwas filtered through a short column of silica gel. The filtrate wasconcentrated and the residue was chromatographed using a mixture ofethyl acetate and hexane as the eluent to give 110 mg of the product(53% yield) as a white solid. ¹ H NMR(300 MHz)δ2.20(qt, 2H), 2.66(t,2H), 3.26(t, 2H), 4.04(s, 3H), 9.72(s, 1H); MS(NH₃ -CI) Calcd. for(M+1)⁺ : 215. Found: 215.

Part E. Methyl[2-[4-[N-Boc--N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carboxylate

Methyl [2-(4-oxobutyl)-1,3,4-thiadiazol-5-yl]carboxylate (100 mg, 0.47mmol) and 2-aminopyridine (48 mg, 0.52 mmol) were dissolved in anhydroustoluene (4 ml) and then were heated at 70° C. for 2 hrs, during whichtime a small amount of pulverised molecular sieve was added. HOAc (30ul, 0.52 mmol) and NaB(OAc)₃ H were added. Stirring was continued at rtfor 18 hrs. NaOAc (300 mg) dissolved in 10 ml of water was added and themixture was diluted with another 10 ml of water after being stirred foradditional 2 hrs. The solution was extracted with CH₂ Cl₂ and theextract was concentrated and dried.

The oily product obtained above was then dissolved in dry CHCl₃ (5 ml),and cooled in an ice-water bath, followed by addition oftriethylamine(0.13 ml, 0.94 mmol), Boc2O(153 mg, 0.71 mmol) and acatalytic amount of DMAP. The mixture was stirred at rt for 24 hrs, andthen diluted with ethyl acetate. The solution was washed with dilutecitric acid, saturated NaHCO₃ and brine successively, and then driedover Na₂ SO₄. Concetration followed by chromatography using a mixture ofethyl acetate and hexane as the eluent afforded the product as an oil(85 mg, 46% yield in two steps). ¹ H NMR(300 MHz)δ1.50(s, 9H), 1.79(qt,2H), 1.84(qt, 2H), 3.20(t, 2H), 4.00(t, 2H), 4.04(s, 3H), 7.00(m, 1H),7.60(m, 2H), 8.38(m, 1H); MS(NH₃ -CI) Calcd. for (M+1)⁺ : 393. Found:393.

Part E.[2-[4-[N-Boc-N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carboxylicacid

Methyl[2-[4-[N-Boc-N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carboxylate(80 mg, 0.20 mmol) dissolved in 0.2 ml of DMSO was mixed with PLE(50 mg)and buffer solution (PH=7.00, 4 ml) and the mixture was vigorouslystirred at rt for 18 hrs, and then was evaporated under high vaccum. Theresulting solid was extracted with ethyl acetate and the extract wasconcentrated to give an oil (60 mg, 78% yield). ¹ H NMR(300 MHz)δ1.52(s,9H), 1.80(qt, 2H), 1.86(qt, 2H), 3.22(t, 2H), 4.00(t, 2H), 7.10(m, 1H),7.64(m, 2H), 8.30(m, 1H); MS(ESI) Calcd. for (M+1)⁺ : 379. Found: 379.

Part F. t-butyl 2(S)-benzyloxycarbonylamino-3-aminopropionate

Conc. H2SO4(8 ml) was added to dioxane(120 ml) in a Parr Bottle cooledwith dry ice, followed by addition of2(S)-benzyloxycarbonylamino-3-aminopropionic acid (6.88 g, 28.8 mmol)and pre-condensed isobutylene (130 ml, excess). The mixture in the Parrbottlle was then shaked at rt for 70 hrs. After removal of isobutyleneunder reduced pressure, the resulting solution was poured into a NaOHsolution containing NaOH (17.4 g) and ether (400 ml) cooled in an icewater bath while stirred vigorously. The etheral layer was separated andthe aqueous layer was extracted with ether. The combined etheralsolution was washed with 1N HaOH twice and then dried over Na₂ SO₄.Concetration gave the product as a solid (6.3 g, 75% yield). ¹ H NMR(300MHz)δ1.44(s, 9H), 3.10(m,2H), 4.26(m, 1H), 5.12(s, 2H), 5.80(d, 1H),7.36(m, 5H); MS(NH₃ -CI) Calcd. for (M+1)⁺ : 293. Found: 293.

Part G. t-Butyl2(S)-Benzyloxycarbonylamino-3-[[2-[4-[N-Boc-N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionate

To a mixture of[2-[4-[N-Boc-N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carboxylicacid (50 mg, 0.13 mmol), t-butyl2(S)-benzyloxycarbonylamino-3-aminopropionate (40 mg, 0,13 mmol) andtriethylamine (40 ul, 0.29 mmol) in EtOAc(4 ml), was added PyBop (75 mg,0.13 mmol). After stirring for 4 hrs at rt, the reaction mixture wasdiluted with ethyl acetate and washed with dilute citric acid, diluteNaHCO₃ and brine successively, then dried. Concentration followed bychromatography using a mixture of ethyl acetate and hexane as the eluentgave the product as an amorphous solid (30 mg, 35% yield).¹ H NMR(300MHz)δ1.46(s, 9H), 1.50(s, 9H), 1.80(m, 4H), 3.19(t, 2H), 3.87(m, 2H),4.00(t, 2H), 4.44(m, 1H), 5.12(s, 2H), 5.68(d, 1H), 7.00(m, 1H), 7.36(m,5H), 7.60(m, 2H), 8.40(m, 1H); MS(ESI) Calc. for (M+1)⁺ : 655. Found:655.

Part H.2(S)-Benzyloxycarbonylamino-3-[[2-[4-[N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

t-Butyl2(S)-Benzyloxycarbonylamino-3-[[2-[4-[N-Boc-N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionate(30 mg, 0.046 mmol) was dissolved in CH₂ Cl₂ (5 ml) containing 0.25 mlof TFA. The solution was stirred at rt for 24 hrs and then concetrated,affording an oily product (20 mg, 87% yield). Further purification byreverse HPLC using a mixture of acetonitrile and 0.1% TFA in water gavethe sample for testing. ¹ H NMR(300 MHz)δ1.68(qt, 2H), 1.84(qt, 2H),3.20(t, 2H), 3.36(m, 2H), 3.64(t, 2H), 4.25(m, 1H), 5.02(s, 2H), 6.84(t,1H), 7.04(d, 1H), 7.54(m, 5H), 7.70(m, 1H), 7.90(m, 2H), 8.80(m, 1H),9.20(t, 1H); MS(ESI) Calc. for (M+1)⁺ : 499. Found: 499.

EXAMPLE 1782(S)-(2,4,6-Trimethylphenylsulfonyl)amino-3-[[2-[4-[N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

Part A. 2-N-Mesitylenesufonyl-L-asparigine

L-Asparagine (8.5 g, 56.8 mmol) was dissolved in water (23 ml)containing triethylamine (19.8 ml). Thi mixture was then diluted withdioxane (40 ml). To the resulting mixture was added slowly2-mesitylenesulfonyl chloride (14.85 g) dissolved in dioxane (50 ml),causing a little exothermic. After addition, the mixure was stirredfurther at rt for 24 hrs. The reaction mixture was evaporated to removemost of the organic solvent, and then basified with 2N HaOH. The basicsolution was extracted with CH2Cl2(50 ml×2) and filtered. The filtratewas acidified with concentrated HCl. The solid formed was collected byfiltration (13.0 g, 73%yield). ¹ H NMR(300 MHz,CDCl₃)δ2.24(s, 3H),2.30(dd, 1H), 2.43(dd, 1H), 2.54(s, 6H), 4.00(m, 1H), 6.86(s, 1H),7.00(s, 2H), 7.32(s, 1H), 7.80(d, 1H); MS(ESI) Calc. for (M+1)⁺ : 315.Found: 315.

Part B. 2(S)-(2,4,6-Trimethylphenylsulfonyl)amino-3-aminopropionic acid

Bromine (1.04 ml, 20.1 ml) was added to a solution of 4N NaOH(34 ml)cooled in an ice-water bath. The orange solution was stirred in the icebath for additional 15 mins and then 2-N-Mesitylenesufonyl-L-asparigine(5.3 g, 16.8 mmol) was added in portions. Stirring was continued in theice bath for 15 mins and then at 85° C. for 1 hr. The resulting solutionwas cooled in an ice bath and acidified with conc. HCl to PH ˜6. Thesolid was collected through filtration (4,7 g, 97% yield). ¹ H NMR(300MHz, DMSO-d₆)δ2.20(s, 3H), 2.48(s, 6H), 2.76(t, 1H), 2.92(m, 1H),3.04(m, 1H), 6.98(s, 1H), 7.00(s, 2H); MS(ESI) Calc. for (M+1)⁺ : 287.Found: 287.

Part C. t-Butyl 2(S)-(2,4,6 trimethylphenylsulfonyl)amino-3-aminopropionate

Conc. H2SO4 (7.7 ml) was added to dioxane (120 ml) in a Parr Bottlecooled with dry ice, followed by addition of2(S)-(2,4,6-trimethylphenylsulfonyl)amino-3-aminopropionic acid(8,02 g,28 mmol) and pre-condensed isobutylene (136 ml, excess). The mixture inthe Parr bottlle was then shaked at rt for 70 hrs. After removal ofisobutylene under reduced pressure, the resulting solution was pouredinto a NaOH solution containing NaOH(11.9 g) and ether (400 ml) cooledin an ice water bath while stirred vigorously. The etheral layer wasseparated and the aqueous layer was extracted with ether. The combinedetheral solution was washed with 1N HaOH twice and then dried over Na₂SO₄. Concetration gave the product as a solid(7.7 g, 81% yield). ¹ HNMR(300 MHz)δ1.56(s, 9H), 2.20(s, 3H), 2.48(s, 6H), 2.76(t, 1H), 2.92(m,1H), 3.04(m, 1H), 6.98(s, 1H), 7.00(s, 2H) ; MS(NH₃ -CI) Calcd. for(M+1)⁺ : 343. Found: 343.

Part D. t-Butyl 2(S)-(2,4,6-trimethylphenylsulfonyl)amino-3-[2-[4-[N-Boc--N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionate

To a mixture of[2-[4-[N-Boc-N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carboxylicacid (135 mg, 0.36 mmol), t-butyl2(S)-(2,4,6-trimethylphenylsulfonyl)amino-3-aminopropionate (120 mg,0.36 mmol) and triethylamine (0.25 ml, 1.8 mmol) in DMF(8 ml), was addedPyBop (210 mg, 0.36 mmol). After stirring for 4 hrs at rt, the reactionmixture was diluted with ethyl acetate and washed with dilute citricacid, dilute NaHCO₃ and brine successively, then dried. Concentrationfollowed by chromatography using a mixture of ethyl acetate and hexaneas the eluent gave the product as an amorphous solid (150 mg, 64%yield).¹ H NMR(300 MHz, CDCl₃)δ1.32(s, 9H), 1.50(s, 9H), 1.82(m, 4H),2.24(s, 3H), 2.64(s, 6H), 3.20(t, 2H), 3.66(m, 1H), 3.80(m, 1H), 4.00(m,3H), 5.60(d, 1H), 6.90(s, 2H), 7.00(m, 1H), 7.60(m, 2H), 8.40(m, 1H);MS(ESI) Calc. for (M+1)⁺ : 703. Found: 703.

Part E.2(S)-(2,4,6-Trimethylphenylsulfonyl)amino-3-[[2-[4-[N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

t-Butyl 2(S)-(2,4,6 trimethylphenylsulfonyl)amino-3-[[2-[4-[N-Boc-N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionate(60 mg, 0.091 mmol) was dissolved in CH₂ Cl₂ (5 ml) containing 0.25 mlof TFA. The solution was stirred at rt for 24 hrs and then concetrated,affording an oily product (42 mg, 90% yield). Further purification byreverse HPLC using a mixture of acetonitrile and 0.1% TFA in water gavethe sample for testing. ¹ H NMR(300 MHz, DMSO-d₆)δ1.64(qt, 2H), 1.80(qt,2H),2.12(s, 3H), 2.46(s, 6H), 3.18(t, 2H), 3.30(m, 2H), 3.50(m, 2H),3.98(m, 1H), 6.80(s, 2H), 6.84(t, 1H), 7.00(d, 1H), 7.86(m, 2H), 8.02(d,1H), 8.76(s, 1H), 8.94(t, 1H); MS(ESI) Calc. for (M+1)⁺ : 547. Found:547.

EXAMPLE 1792(S)-(1-Naphthalenesulfonyl)amino-3-[[2-[4-[N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

This compound was analogously prepared to Example 178. ¹ H NMR(300 MHz,DMSO-d₆)δ1.64(qt, 2H), 1.80(qt, 2H), 3.18(t, 2H), 3.34(m, 2H), 3.44(m,2H), 3.90(m, 1H), 6.80(t, 1H), 7.00(d, 1H), 7.50(m, 3H), 7.88(m, 3H),8.06(d, d, 2H), 8.56(d, 2H), 8.76(s, 1H), 8.84(t, 1H); MS(ESI) Calc. for(M+1)⁺ : 555. Found: 555.

EXAMPLE 3212(S)-Benzyloxycarbonylamino-3-[[2-[4-[(N-imidazolin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

Part A. Methyl [2-(4-triazobutyl)-1,3,4-thiadiazol-5-yl]carboxylate

Mesyl chloride(0.26 mL, 3.34 mmol) was added slowly to a solution ofmethyl [2-(4-hydroxybutyl)-1,3,4-thiadiazol-5-yl]carboxylate (600 mg,2.78 mmol) and triethylamine (0.77 ml, 5.56 mmol) in CH₂ Cl₂ cooled in aice-water bath. After addition, the resulting mixture was stirred foradditional 30 mins. The reaction mixture was diluted with ethyl acetateand then washed with aqueous citric acid, saturated NaHCO₃ and brine.Concentration and chromatography with a mixture of ethyl acetate andhexane gave the mesylate as an oil (530 mg).

The mesylate was dissolved in DMF(10 ml). Sodium triazide(585 mg, 9.0mmol) was added. The mixture was heated at 40° C. for 4 hrs. Afterdilution with ethyl acetate, the organic solution was washed withsaturated NaHCO₃, brine and then dried over Na₂ SO₄. Concetration andChromatography with a mixture of ethyl aceate and hexane gave 450 mg ofthe product as an oil (67% yield). ¹ H NMR(300 MHz, CDCl₃)δ1.74(m, 2H),1.96(m, 2H), 3.24(t, 2H), 3.38(t, 2H),4.06(s, 1H); MS(NH₃ -CI) Calcd.for (M+1)⁺ : 242. Found: 242.

Part B. [2-(4-triazobutyl)-1,3,4-thiadiazol-5-yl]carboxylic acid

Methyl [2-[4-triazobutyl]-1,3,4-thiadiazol-5-yl]carboxylate (300 mg,1.24 mmol) was mixed with PLE-A(200 mg) and buffer solution(PH=7.00, 10ml). The mixture was vigorously stirred at rt for 36 hrs, and thenevaporated under high vaccum to dryness. The residue was extracted withmethanol and the extract was concentrated to give the aciod as an oil(190 mg, 70% yield). ¹ H NMR(300 MHz, DMSO-d₆)δ1.58(m, 2H), 1.76(m, 2H),3.00(t, 2H), 3.40(t, 2H); MS(ESI) Calcd. for (M+1)⁺ : 228. Found: 228.

Part C. t-Butyl2(S)-benzyloxycarbonylamino-3-[[2-(4-triazobutyl)-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionate

To a mixture of [2-(4-triazobutyl)-1,3,4-thiadiazol-5-yl]carboxylicacid(270 mg, 1.2 mmol), t-butyl2(S)-benzyloxycarbonylamino-3-aminopropionate (350 mg, 0,13 mmol) andtriethylamine (40 ul, 1.2 mmol) in DMF(10 ml), was added PyBop(700 mg,1.2 mmol). After stirring for 4 hrs at rt, the reaction mixture wasdiluted with ethyl acetate and washed with dilute citric acid, diluteNaHCO₃ and brine successively, then dried. Concentration followed bychromatography using a mixture of ethyl acetate and hexane as the eluentgave the product as an amorphous solid(440 mg, 90% yield).¹ H NMR(300MHz, CDCl₃)δ1.40(s, 9H), 1.74(m, 2H), 1.85(m, 2H), 3.20(t, 2H), 3.26(t,2H), 3.88(m, 2H), 4.10(m, 1H), 5.12(S, 2H), 5.80(s, 1H), 7.38(m, 5H),7.68(s, 1H); MS(ESI) Calc. for (M+1)⁺ : 604. Found: 604.

Part D. t-Butyl2(S)-benzyloxycarbonylamino-3-[[2-(4-aminobutyl)-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionate

A solution of t-Butyl2(S)-benzyloxycarbonylamino-3-[[2-(4-triazobutyl)-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionate(240 mg, 0.48 mmol), triphenylphosphine (125 mg, 0.48 mmol) in THF(10ml) was heated to reflux for 3 hrs and then stirred at rt overnight.Water(10 mg, 0.55 mmol) was injected and the reaction mixture wasstirred at rt for additional 24 hrs. Concentration followed bychromatography with a mixture of CH₂ Cl₂, methanol and ammoniumhydroxide gave the product as an oil(150 mg, 66% yield). ¹ H NMR(300MHz, DMSO-d₆)δ1.28(s, 9H), 1.40(m, 2H), 1.70(m, 2H), 2.54(t, 2H),3.10(t, 2H), 3.72(m, 1H), 3.84(m, 1H), 4.20(m, 1H), 5.00(s, 2H), 7.30(m,5H), 7.76(d, 1H); MS(ESI) Calc. for (M+1)⁺ : 478. Found: 478.

Part E. t-Butyl2(S)-Benzyloxycarbonylamino-3-[[2-[4-[(N-imidazolin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionate

A mixture of t-Butyl2(S)benzyloxycarbonylamino-3-[[2-(4-triazobutyl)-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionate(100 mg, 0.21 mmol) and 2-imidazolidinethione hydrogen iodide (61 mg,0.25 mmol) in pyridine (5 mL) was stirred at 70° C. for 3 hrs.Concentration and chromatography with a mixture of CH₂ Cl₂ and methanolas the eluent gave the product as an amorphous solid (60 mg, 53% yield).¹ H NMR(300 MHz, DMSO-d₆)δ1.28(s, 9H), 1.54(m, 2H), 1.76(m, 2H), 3.10(t,2H), 3.42(m, 2H), 3.60(m, 2H), 4.20(m, 1H), 5.00(s, 2H), 7.30(m, 5H),7.78(d, 1H), 8.20(t, 1H), 9.20(t, 1H); MS(ESI) Calc. for (M+1)⁺ : 546.Found: 546.

Part E,2(S)-Benzyloxycarbonylamino-3-[[2-[4-[(N-imidazolin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

t-Butyl2(S)-benzyloxycarbonylamino-3-[[2-[4-[(N-imidazolin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionate(100 mg, 0.18 mmol) was dissolved in CH₂ Cl₂ containg 0.25 mL of TFA.The solution was stirred at rt for 24 hrs. Concentration gave theproduct(80 mg, 89% yield). ¹ H NMR(300 MHz, DMSO-d₆)δ1.56(m, 2H),1.86(m, 2H), 3.18(m, 4H), 3.54(m, 1H), 3.58(s, 4H), 3.66(m, 1H), 4.10(m,1H), 5.00(s, 2H), 7.30(m, 5H), 7.76(d, 1H), 8.16(t, 1H), 9.10(t, 1H);MS(ESI) Calc. for (M+1)⁺ : 491. Found: 491.

EXAMPLE 3272(S)-(2,4,6-Trimethylphenylsulfonyl)amino-3-[[2-[4-[(N-imidazolin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

This compound was analogously synthesized to Example 321.

¹ H NMR(300 MHz, DMSO-d₆)1.54(m, 2H), 1.76(m, 2H), 2.20(s, 3H), 2.60(s,6H), 3.10(m, 4H), 3.42(m, 1H), 3.60(m, 1H) , 3.82(s, 4H), 4.20(m, 1H),6.98(s, 2H), 7.40(d, 2H) 7.78(d, 1H), 8.20(t, 1H), 9.20(t, 1H); MS(ESI)Calc. for (M+1)⁺ : 538. Found: 538.

EXAMPLE 3302(S)-(1-Naphthalenesulfonyl)amino-3-[[2-[4-[(N-imidazolin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt

This compound was analogously synthesized to Example 321.

¹ H NMR(300 MHz, DMSO-d₆)δ1.56(m, 2H), 1.74(m, 2H), 3.14(m, 4H), 3.38(m,1H), 3.48(m, 1H), 3.58(s, 4H), 4.08(m, 1H), 7.60(m, 4H), 7.98(d, 1H),8.06(d, 1H), 8.16(m, 2H), 8.58(d, 1H), 8.70(d, 1H), 9.12(t, 1H); MS(ESI)Calc. for (M+1)⁺ : 546. Found: 546.

                  TABLE 1                                                         ______________________________________                                         ##STR18##                                                                    Ex.                                                                           No.  R.sup.1 -U   m     n   R.sup.8                                                                            R.sup.9    MS                                ______________________________________                                         1   tetrahydropyrimidin-                                                                       3     1   H    H                                                 2-ylamino                                                                 2   tetrahydropyrimidin-                                                                       3     1   H    NHCbz                                             2-ylamino                                                                 3   tetrahydropyrimidin-                                                                       3     1   H    NHtBOC                                            2-ylamino                                                                 4   tetrahydropyrimidin-                                                                       3     1   H    NHCO.sub.2 -nBu                                   2-ylamino                                                                 5   tetrahydropyrimidin-                                                                       3     1   H    NHCO.sub.2 Et                                     2-ylamino                                                                 6   tetrahydropyrimidin-                                                                       3     1   H    NHCO.sub.2 Me                                     2-ylamino                                                                 7   tetrahydropyrimidin-                                                                       3     1   H    NHCO(CH.sub.2).sub.n Ph                           2-ylamino                                                                 8   tetrahydropyrimidin-                                                                       3     1   H    NHCOtBu                                           2-ylamino                                                                 9   tetrahydropyrimidin-                                                                       3     1   H    NHCO-n-C.sub.5 H.sub.11                           2-ylamino                                                                 10  tetrahydropyrimidin-                                                                       3     1   H    NHCO-n-C.sub.4 H.sub.9                            2-ylamino                                                                 11  tetrahydropyrimidin-                                                                       3     1   H    NHCOCH.sub.2 CH.sub.3                             2-ylamino                                                                 12  tetrahydropyrimidin-                                                                       3     1   H    NHCOCH.sub.3                                      2-ylamino                                                                 13  tetrahydropyrimidin-                                                                       3     1   H    NHSO.sub.2 CH.sub.3                               2-ylamino                                                                 14  tetrahydropyrimidin-                                                                       3     1   H    NHSO.sub.2 CH.sub.2 CH.sub.3                      2-ylamino                                                                 15  tetrahydropyrimidin-                                                                       3     1   H    NHSO.sub.2 n-Bu                                   2-ylamino                                                                 16  tetrahydropyrimidin-                                                                       3     1   H    NHSO.sub.2 Ph                                     2-ylamino                                                                 17  tetrahydropyrimidin-                                                                       3     1   H    NHSO.sub.2 C.sub.6 H.sub.4                        2-ylamino                   (4-CH.sub.3)                                  18  tetrahydropyrimidin-                                                                       3     1   H    NHSO.sub.2 Bn                                     2-ylamino                                                                 19  tetrahydropyrimidin-                                                                       3     1   H    NHCO (2-pyridyl)                                  2-ylamino                                                                 20  tetrahydropyrimidin-                                                                       3     1   H    NHCO (3-pyridyl)                                  2-ylamino                                                                 21  tetrahydropyrimidin-                                                                       3     1   H    NHCO (4-pyridyl)                                  2-ylamino                                                                 22  tetrahydropyrimidin-                                                                       3     1   H    NHCOCH.sub.2                                      2-ylamino                   (2-pyridyl)                                   23  tetrahydropyrimidin-                                                                       3     1   H    NHCOCH.sub.2                                      2-ylamino                   (3-pyridyl)                                   24  tetrahydropyrimidin-                                                                       3     1   H    NHCOCH.sub.2                                      2-ylamino                   (4-pyridyl)                                   25  tetrahydropyrimidin-                                                                       3     1   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (2-pyridyl)                                   26  tetrahydropyrimidin-                                                                       3     1   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (3-pyridyl)                                   27  tetrahydropyrimidin-                                                                       3     1   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (4-pyridyl)                                   28  imidazolin-2-                                                                              3     1   H    H                                                 ylamino                                                                   29  imidazolin-2-                                                                              3     1   H    NHCbz                                             ylamino                                                                   30  imidazolin-2-                                                                              3     1   H    NHtBOC                                            ylamino                                                                   31  imidazolin-2-                                                                              3     1   H    NHCO.sub.2 -nBu                                   ylamino                                                                   32  imidazolin-2-                                                                              3     1   H    NHCO.sub.2 Et                                     ylamino                                                                   33  imidazolin-2-                                                                              3     1   H    NHCO.sub.2 Me                                     ylamino                                                                   34  imidazolin-2-                                                                              3     1   H    NHCO(CH.sub.2).sub.n Ph                           ylamino                                                                   35  imidazolin-2-                                                                              3     1   H    NHCOtBu                                           ylamino                                                                   36  imidazolin-2-                                                                              3     1   H    NHCO-n-C.sub.5 H.sub.11                           ylamino                                                                   37  imidazolin-2-                                                                              3     1   H    NHCO-n-C.sub.4 H.sub.9                            ylamino                                                                   38  imidazolin-2-                                                                              3     1   H    NHCOCH.sub.2 CH.sub.3                             ylamino                                                                   39  imidazolin-2-                                                                              3     1   H    NHCOCH.sub.3                                      ylamino                                                                   40  imidazolin-2-                                                                              3     1   H    NHSO.sub.2 CH.sub.3                               ylamino                                                                   41  imidazolin-2-                                                                              3     1   H    NHSO.sub.2 CH.sub.2 CH.sub.3                      ylamino                                                                   42  imidazolin-2-                                                                              3     1   H    NHSO.sub.2 n-Bu                                   ylamino                                                                   43  imidazolin-2-                                                                              3     1   H    NHSO.sub.2 Ph                                                                            496                                    ylamino                                                                   44  imidazolin-2-                                                                              3     1   H    NHSO.sub.2 C.sub.6 H.sub.4                                                               510                                    ylamino                     (3-CH.sub.3)                                  45  imidazolin-2-                                                                              3     1   H    NHSO.sub.2 Bn                                     ylamino                                                                   46  imidazolin-2-                                                                              3     1   H    NHCO (2-pyridyl)                                  ylamino                                                                   47  imidazolin-2-                                                                              3     1   H    NHCO (3-pyridyl)                                  ylamino                                                                   48  imidazolin-2-                                                                              3     1   H    NHCO (4-pyridyl)                                  ylamino                                                                   49  imidazolin-2-                                                                              3     1   H    NHCOCH.sub.2                                      ylamino                     (2-pyridyl)                                   50  imidazolin-2-                                                                              3     1   H    NHCOCH.sub.2                                      ylamino                     (3-pyridyl)                                   51  imidazolin-2-                                                                              3     1   H    NHCOCH.sub.2                                      ylamino                     (4-pyridyl)                                   52  imidazolin-2-                                                                              3     1   H    NHCO.sub.2 CH.sub.2                               ylamino                     (2-pyridyl)                                   53  imidazolin-2-                                                                              3     1   H    NHCO.sub.2 CH.sub.2                               ylamino                     (3-pyridyl)                                   54  imidazolin-2-                                                                              3     1   H    NHCO.sub.2 CH.sub.2                               ylamino                     (4-pyridyl)                                   55  tetrahydropyrimidin-                                                                       4     0   H    H                                                 2-ylamino                                                                 56  tetrahydropyrimidin-                                                                       4     0   H    NHCbz                                             2-ylamino                                                                 57  tetrahydropyrimidin-                                                                       4     0   H    NHtBOC                                            2-ylamino                                                                 58  tetrahydropyrimidin-                                                                       4     0   H    NHCO.sub.2 -nBu                                   2-ylamino                                                                 59  tetrahydropyrimidin-                                                                       4     0   H    NHCO.sub.2 Et                                     2-ylamino                                                                 60  tetrahydropyrimidin-                                                                       4     0   H    NHCO.sub.2 Me                                     2-ylamino                                                                 61  tetrahydropyrimidin-                                                                       4     0   H    NHCO(CH.sub.2).sub.n Ph                           2-ylamino                                                                 62  tetrahydropyrimidin-                                                                       4     0   H    NHCOtBu                                           2-ylamino                                                                 63  tetrahydropyrimidin-                                                                       4     0   H    NHCO-n-C.sub.5 H.sub.11                           2-ylamino                                                                 64  tetrahydropyrimidin-                                                                       4     0   H    NHCO-n-C.sub.4 H.sub.9                            2-ylamino                                                                 65  tetrahydropyrimidin-                                                                       4     0   H    NHCOCH.sub.2 CH.sub.3                             2-ylamino                                                                 66  tetrahydropyrimidin-                                                                       4     0   H    NHCOCH.sub.3                                      2-ylamino                                                                 67  tetrahydropyrimidin-                                                                       4     0   H    NHSO.sub.2 CH.sub.3                               2-ylamino                                                                 68  tetrahydropyrimidin-                                                                       4     0   H    NHSO.sub.2 CH.sub.2 CH.sub.3                      2-ylamino                                                                 69  tetrahydropyrimidin-                                                                       4     0   H    NHSO.sub.2 n-Bu                                   2-ylamino                                                                 70  tetrahydropyrimidin-                                                                       4     0   H    NHSO.sub.2 Ph                                     2-ylamino                                                                 71  tetrahydropyrimidin-                                                                       4     0   H    NHSO.sub.2 C.sub.6 H.sub.4                        2-ylamino                   (4-CH.sub.3)                                  72  tetrahydropyrimidin-                                                                       4     0   H    NHSO.sub.2 Bn                                     2-ylamino                                                                 73  tetrahydropyrimidin-                                                                       4     0   H    NHCO (2-pyridyl)                                  2-ylamino                                                                 74  tetrahydropyrimidin-                                                                       4     0   H    NHCO (3-pyridyl)                                  2-ylamino                                                                 75  tetrahydropyrimidin-                                                                       4     0   H    NHCO (4-pyridyl)                                  2-ylamino                                                                 76  tetrahydropyrimidin-                                                                       4     0   H    NHCOCH.sub.2                                      2-ylamino                   (2-pyridyl)                                   77  tetrahydropyrimidin-                                                                       4     0   H    NHCOCH.sub.2                                      2-ylamino                   (3-pyridyl)                                   78  tetrahydropyrimidin-                                                                       4     0   H    NHCOCH.sub.2                                      2-ylamino                   (4-pyridyl)                                   79  tetrahydropyrimidin-                                                                       4     0   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (2-pyridyl)                                   80  tetrahydropyrimidin-                                                                       4     0   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (3-pyridyl)                                   81  tetrahydropyrimidin-                                                                       4     0   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (4-pyridyl)                                   82  imidazolin-2-                                                                              4     0   H    H                                                 ylamino                                                                   83  imidazolin-2-                                                                              4     0   H    NHCbz                                             ylamino                                                                   84  imidazolin-2-                                                                              4     0   H    NHtBOC                                            ylamino                                                                   85  imidazolin-2-                                                                              4     0   H    NHCO.sub.2 -nBu                                   ylamino                                                                   86  imidazolin-2-                                                                              4     0   H    NHCO.sub.2 Et                                     ylamino                                                                   87  imidazolin-2-                                                                              4     0   H    NHCO.sub.2 Me                                     ylamino                                                                   88  imidazolin-2-                                                                              4     0   H    NHCO(CH.sub.2).sub.n Ph                           ylamino                                                                   89  imidazolin-2-                                                                              4     0   H    NHCOtBu                                           ylamino                                                                   90  imidazolin-2-                                                                              4     0   H    NHCO-n-C.sub.5 H.sub.11                           ylamino                                                                   91  imidazolin-2-                                                                              4     0   H    NHCO-n-C.sub.4 H.sub.9                            ylamino                                                                   92  imidazolin-2-                                                                              4     0   H    NHCOCH.sub.2 CH.sub.3                             ylamino                                                                   93  imidazolin-2-                                                                              4     0   H    NHCOCH.sub.3                                      ylamino                                                                   94  imidazolin-2-                                                                              4     0   H    NHSO.sub.2 CH.sub.3                               ylamino                                                                   95  imidazolin-2-                                                                              4     0   H    NHSO.sub.2 CH.sub.2 CH.sub.3                      ylamino                                                                   96  imidazolin-2-                                                                              4     0   H    NHSO.sub.2 n-Bu                                   ylamino                                                                   97  imidazolin-2-                                                                              4     0   H    NHSO.sub.2 Ph                                     ylamino                                                                   98  imidazolin-2-                                                                              4     0   H    NHSO.sub.2 C.sub.6 H.sub.4                        ylamino                     (4-CH.sub.3)                                  99  imidazolin-2-                                                                              4     0   H    NHSO.sub.2 Bn                                     ylamino                                                                  100  imidazolin-2-                                                                              4     0   H    NHCO (2-pyridyl)                                  ylamino                                                                  101  imidazolin-2-                                                                              4     0   H    NHCO (3-pyridyl)                                  ylamino                                                                  102  imidazolin-2-                                                                              4     0   H    NHCO (4-pyridyl)                                  ylamino                                                                  103  imidazolin-2-                                                                              4     0   H    NHCOCH.sub.2                                      ylamino                     (2-pyridyl)                                  104  imidazolin-2-                                                                              4     0   H    NHCOCH.sub.2                                      ylamino                     (3-pyridyl)                                  105  imidazolin-2-                                                                              4     0   H    NHCOCH.sub.2                                      ylamino                     (4-pyridyl)                                  106  imidazolin-2-                                                                              4     0   H    NHCO.sub.2 CH.sub.2                               ylamino                     (2-pyridyl)                                  107  imidazolin-2-                                                                              4     0   H    NHCO.sub.2 CH.sub.2                               ylamino                     (3-pyridyl)                                  108  imidazolin-2-                                                                              4     0   H    NHCO.sub.2 CH.sub.2                               ylamino                     (4-pyridyl)                                  109  tetrahydropyrimidin-                                                                       3     0   H    H                                                 2-ylamino                                                                110  tetrahydropyrimidin-                                                                       3     0   H    NHCbz                                             2-ylamino                                                                111  tetrahydropyrimidin-                                                                       3     0   H    NHtBOC                                            2-ylamino                                                                112  tetrahydropyrimidin-                                                                       3     0   H    NHCO.sub.2 -nBu                                   2-ylamino                                                                113  tetrahydropyrimidin-                                                                       3     0   H    NHCO.sub.2 Et                                     2-ylamino                                                                114  tetrahydropyrimidin-                                                                       3     0   H    NHCO.sub.2 Me                                     2-ylamino                                                                115  tetrahydropyrimidin-                                                                       3     0   H    NHCO(CH.sub.2).sub.n Ph                           2-ylamino                                                                116  tetrahydropyrimidin-                                                                       3     0   H    NHCOtBu                                           2-ylamino                                                                117  tetrahydropyrimidin-                                                                       3     0   H    NHCO-n-C.sub.5 H.sub.11                           2-ylamino                                                                118  tetrahydropyrimidin-                                                                       3     0   H    NHCO-n-C.sub.4 H.sub.9                            2-ylamino                                                                119  tetrahydropyrimidin-                                                                       3     0   H    NHCOCH.sub.2 CH.sub.3                             2-ylamino                                                                120  tetrahydropyrimidin-                                                                       3     0   H    NHCOCH.sub.3                                      2-ylamino                                                                121  tetrahydropyrimidin-                                                                       3     0   H    NHSO.sub.2 CH.sub.3                               2-ylamino                                                                122  tetrahydropyrimidin-                                                                       3     0   H    NHSO.sub.2 CH.sub.2 CH.sub.3                      2-ylamino                                                                123  tetrahydropyrimidin-                                                                       3     0   H    NHSO.sub.2 n-Bu                                   2-ylamino                                                                124  tetrahydropyrimidin-                                                                       3     0   H    NHSO.sub.2 Ph                                     2-ylamino                                                                125  tetrahydropyrimidin-                                                                       3     0   H    NHSO.sub.2 C.sub.6 H.sub.4                        2-ylamino                   (4-CH.sub.3)                                 126  tetrahydropyrimidin-                                                                       3     0   H    NHSO.sub.2 Bn                                     2-ylamino                                                                127  tetrahydropyrimidin-                                                                       3     0   H    NHCO (2-pyridyl)                                  2-ylamino                                                                128  tetrahydropyrimidin-                                                                       3     0   H    NHCO (3-pyridyl)                                  2-ylamino                                                                129  tetrahydropyrimidin-                                                                       3     0   H    NHCO (4-pyridyl)                                  2-ylamino                                                                130  tetrahydropyrimidin-                                                                       3     0   H    NHCOCH.sub.2                                      2-ylamino                   (2-pyridyl)                                  131  tetrahydropyrimidin-                                                                       3     0   H    NHCOCH.sub.2                                      2-ylamino                   (3-pyridyl)                                  132  tetrahydropyrimidin-                                                                       3     0   H    NHCOCH.sub.2                                      2-ylamino                   (4-pyridyl)                                  133  tetrahydropyrimidin-                                                                       3     0   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (2-pyridyl)                                  134  tetrahydropyrimidin-                                                                       3     0   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (3-pyridyl)                                  135  tetranydropyrimidin-                                                                       3     0   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (4-pyridyl)                                  136  imidazolin-2-                                                                              3     0   H    H                                                 ylamino                                                                  137  imidazolin-2-                                                                              3     0   H    NHCbz                                             ylamino                                                                  138  imidazolin-2-                                                                              3     0   H    NHtBOC                                            ylamino                                                                  139  imidazolin-2-                                                                              3     0   H    NHCO.sub.2 -nBu                                   ylamino                                                                  140  imidazolin-2-                                                                              3     0   H    NHCO.sub.2 Et                                     ylamino                                                                  141  imidazolin-2-                                                                              3     0   H    NHCO.sub.2 Me                                     ylamino                                                                  142  imidazolin-2-                                                                              3     0   H    NHCO(CH.sub.2).sub.n Ph                           ylamino                                                                  143  imidazolin-2-                                                                              3     0   H    NHCOtBu                                           ylamino                                                                  144  imidazolin-2-                                                                              3     0   H    NHCO-n-C.sub.5 H.sub.11                           ylamino                                                                  145  imidazolin-2-                                                                              3     0   H    NHCO-n-C.sub.4 H.sub.9                            ylamino                                                                  146  imidazolin-2-                                                                              3     0   H    NHCOCH.sub.2 CH.sub.3                             ylamino                                                                  147  imidazolin-2-                                                                              3     0   H    NHCOCH.sub.3                                      ylamino                                                                  148  imidazolin-2-                                                                              3     0   H    NHSO.sub.2 CH.sub.3                               ylamino                                                                  149  imidazolin-2-                                                                              3     0   H    NHSO.sub.2 CH.sub.2 CH.sub.3                      ylamino                                                                  150  imidazolin-2-                                                                              3     0   H    NHSO.sub.2 n-Bu                                   ylamino                                                                  151  imidazolin-2-                                                                              3     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  152  imidazolin-2-                                                                              3     0   H    NHSO.sub.2 C.sub.6 H.sub.4                        ylamino                     (4-CH.sub.3)                                 153  imidazolin-2-                                                                              3     0   H    NHSO.sub.2 Bn                                     ylamino                                                                  154  imidazolin-2-                                                                              3     0   H    NHCO (2-pyridyl)                                  ylamino                                                                  155  imidazolin-2-                                                                              3     0   H    NHCO (3-pyridyl)                                  ylamino                                                                  156  imidazolin-2-                                                                              3     0   H    NHCO (4-pyridyl)                                  ylamino                                                                  157  imidazolin-2-                                                                              3     0   H    NHCOCH.sub.2                                      ylamino                     (2-pyridyl)                                  158  imidazolin-2-                                                                              3     0   H    NHCOCH.sub.2                                      ylamino                     (3-pyridyl)                                  159  imidazolin-2-                                                                              3     0   H    NHCOCH.sub.2                                      ylamino                     (4-pyridyl)                                  160  imidazolin-2-                                                                              3     0   H    NHCO.sub.2 CH.sub.2                               ylamino                     (2-pyridyl)                                  161  imidazolin-2-                                                                              3     0   H    NHCO.sub.2 CH.sub.2                               ylamino                     (3-pyridyl)                                  162  imidazolin-2-                                                                              3     0   H    NHCO.sub.2 CH.sub.2                               ylamino                     (4-pyridyl)                                  163  4,1,3-oxadiazin-2-                                                                         4     0   H    NHCbz                                             ylamino                                                                  164  4,1,3-oxadiazin-2-                                                                         4     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  165  4,1,3-oxadiazin-2-                                                                         4     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  166  4,1,3-oxadiazin-2-                                                                         4     0   H    NHSO.sub.2 -n-Bu                                  ylamino                                                                  167  4,1,3-oxadiazin-2-                                                                         3     1   H    NHCbz                                             ylamino                                                                  168  4,1,3-oxadiazin-2-                                                                         3     1   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  169  4,1,3-oxadiazin-2-                                                                         3     1   H    NHSO.sub.2 Ph                                     ylamino                                                                  170  4,1,3-oxadiazin-2-                                                                         3     1   H    NHSO.sub.2 -n-Bu                                  ylamino                                                                  172  pyridin-2-ylamino                                                                          3     1   H    NHCbz                                        173  pyridin-2-ylamino                                                                          3     1   H    NHCO.sub.2 -n-Bu                             174  pyridin-2-ylamino                                                                          3     1   H    NHSO.sub.2 Ph                                175  pyridin-2-ylamino                                                                          3     1   H    NHSO.sub.2 -nBu                              176  pyridin-2-ylamino                                                                          4     0   H    NHCbz      499                               177  pyridin-2-ylamino                                                                          4     0   H    NHCO.sub.2 -n-Bu                             178  pyridin-2-ylamino                                                                          4     0   H    (2,4,6-trimethyl-                                                                        547                                                                phenylsulfonyl)-                                                              amino                                        179  pyridin-2-ylamino                                                                          4     0   H    (1-naphthalene-                                                                          555                                                                sulfonyl)amino                               180  pyridin-2-ylamino                                                                          3     0   H    NHCbz                                        181  pyridin-2-ylamino                                                                          3     0   H    NHCO.sub.2 -n-Bu                             182  pyridin-2-ylamino                                                                          3     0   H    NHSO.sub.2 Ph                                183  pyridin-2-ylamino                                                                          3     0   H    NHSO.sub.2 -nBu                              184  imidazol-2-ylamino                                                                         3     1   H    NHCbz                                        185  imidazol-2-ylamino                                                                         3     1   H    NHCO.sub.2 -n-Bu                             186  imidazol-2-ylamino                                                                         3     1   H    NHSO.sub.2 Ph                                187  imidazol-2-ylamino                                                                         3     1   H    NHSO.sub.2 -nBu                              188  imidazol-2-ylamino                                                                         4     0   H    NHCbz                                        189  imidazol-2-ylamino                                                                         4     0   H    NHCO.sub.2 -n-Bu                             190  imidazol-2-ylamino                                                                         4     0   H    NHSO.sub.2 Ph                                191  imidazol-2-ylamino                                                                         4     0   H    NHSO.sub.2 -nBu                              192  imidazol-2-ylamino                                                                         3     0   H    NHCbz                                        193  imidazol-2-ylamino                                                                         3     0   H    NHCO.sub.2 -n-Bu                             194  imidazol-2-ylamino                                                                         3     0   H    NHSO.sub.2 Ph                                195  imidazol-2-ylamino                                                                         3     0   H    NHSO.sub.2 -nBu                              196  thiazol-2-ylamino                                                                          3     1   H    NHCbz                                        197  2-aminopyridin-6-yl                                                                        3     1   H    NHCO.sub.2 -n-Bu                             198  2-aminopyridin-6-yl                                                                        3     1   H    NHSO.sub.2 Ph                                199  2-aminopyridin-6-yl                                                                        3     1   H    NHSO.sub.2 -nBu                              200  2-aminopyridin-6-yl                                                                        4     0   H    NHCbz                                        201  2-aminopyridin-6-yl                                                                        4     0   H    NHCO.sub.2 -n-Bu                             202  2-aminopyridin-6-yl                                                                        4     0   H    NHSO.sub.2 Ph                                203  2-aminopyridin-6-yl                                                                        4     0   H    NHSO.sub.2 -nBu                              204  2-aminopyridin-6-yl                                                                        3     0   H    NHCbz                                        205  2-aminopyridin-6-yl                                                                        3     0   H    NHCO.sub.2 -n-Bu                             206  2-aminopyridin-6-yl                                                                        3     0   H    NHSO.sub.2 Ph                                207  2-aminopyridin-6-yl                                                                        3     0   H    NHSO.sub.2 -nBu                              208  2-aminopyridin-3-yl                                                                        2     0   H    NHCbz                                        209  2-aminopyridin-3-yl                                                                        2     0   H    NHCO.sub.2 -n-Bu                             210  2-aminopyridin-3-yl                                                                        2     0   H    NHSO.sub.2 Ph                                211  2-aminopyridin-3-yl                                                                        2     0   H    NHSO.sub.2 -nBu                              212  2-aminothiazol-4-yl                                                                        3     1   H    NHCbz                                        213  2-aminothiazol-4-yl                                                                        3     1   H    NHCO.sub.2 -n-Bu                             214  2-aminothiazol-4-yl                                                                        3     1   H    NHSO.sub.2 Ph                                215  2-aminothiazol-4-yl                                                                        3     1   H    NHSO.sub.2 -nBu                              216  2-aminothiazol-4-yl                                                                        4     0   H    NHCbz                                        217  2-aminothiazol-4-yl                                                                        4     0   H    NHCO.sub.2 -n-Bu                             218  2-aminothiazol-4-yl                                                                        4     0   H    NHSO.sub.2 Ph                                219  2-aminopyridin-6-yl                                                                        4     0   H    NHSO.sub.2 -nBu                              220  2-aminothiazol-4-yl                                                                        3     0   H    NHCbz                                        221  2-aminothiazol-4-yl                                                                        3     0   H    NHCO.sub.2 -n-Bu                             222  2-aminothiazol-4-yl                                                                        3     0   H    NHSO.sub.2 Ph                                223  2-aminothiazol-4-yl                                                                        3     0   H    NHSO.sub.2 -nBu                              224  2-aminothiazol-4-yl                                                                        3     1   H    NHCbz                                        225  2-aminothiazol-4-yl                                                                        3     1   H    NHCO.sub.2 -n-Bu                             226  1,3,4-thiadiazol-2-                                                                        3     1   H    NHSO.sub.2 Ph                                     ylamino                                                                  227  1,3,4-thiadiazol-2-                                                                        3     1   H    NHSO.sub.2 -nBu                                   ylamino                                                                  228  1,3,4-thiadiazol-2-                                                                        4     0   H    NHCbz                                             ylamino                                                                  229  1,3,4-thiadiazol-2-                                                                        4     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  230  1,3,4-thiadiazol-2-                                                                        4     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  231  1,3,4-thiadiazol-2-                                                                        4     0   H    NHSO.sub.2 -nBu                                   ylamino                                                                  232  1,3,4-thiadiazol-2-                                                                        3     0   H    NHCbz                                             ylamino                                                                  233  1,3,4-thiadiazol-2-                                                                        3     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  234  1,3,4-thiadiazol-2-                                                                        3     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  235  1,2,4-thiadiazol-5-                                                                        3     0   H    NHSO.sub.2 -nBu                                   ylamino                                                                  236  1,2,4-thiadiazol-5-                                                                        3     1   H    NHCbz                                             ylamino                                                                  237  1,2,4-thiadiazol-5-                                                                        3     1   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  238  1,2,4-thiadiazol-5-                                                                        3     1   H    NHSO.sub.2 Ph                                     ylamino                                                                  239  1,2,4-thiadiazol-5-                                                                        3     1   H    NHSO.sub.2 -nBu                                   ylamino                                                                  240  1,2,4-thiadiazol-5-                                                                        4     0   H    NHCbz                                             ylamino                                                                  241  1,2,4-thiadiazol-5-                                                                        4     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  242  1,2,4-thiadiazol-5-                                                                        4     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  243  1,2,4-thiadiazol-5-                                                                        4     0   H    NHSO.sub.2 -nBu                                   ylamino                                                                  244  1,2,4-thiadiazol-5-                                                                        3     0   H    NHCbz                                             ylamino                                                                  245  1,2,4-thiadiazol-5-                                                                        3     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  246  1,2,4-thiadiazol-5-                                                                        3     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  247  isoxazol-3-ylamino                                                                         3     0   H    NHSO.sub.2 -nBu                              248  isoxazol-3-ylamino                                                                         3     1   H    NHCbz                                        249  isoxazol-3-ylamino                                                                         3     1   H    NHCO.sub.2 -n-Bu                             250  isoxazol-3-ylamino                                                                         3     1   H    NHSO.sub.2 Ph                                251  isoxazol-3-ylamino                                                                         3     1   H    NHSO.sub.2 -nBu                              252  isoxazol-3-ylamino                                                                         4     0   H    NHCbz                                        253  isoxazol-3-ylamino                                                                         4     0   H    NHCO.sub.2 -n-Bu                             254  isoxazol-3-ylamino                                                                         4     0   H    NHSO.sub.2 Ph                                255  isoxazol-3-ylamino                                                                         4     0   H    NHSO.sub.2 -nBu                              256  isoxazol-3-ylamino                                                                         3     0   H    NHCbz                                        257  isoxazol-3-ylamino                                                                         3     0   H    NHCO.sub.2 -n-Bu                             258  isoxazol-3-ylamino                                                                         3     0   H    NHSO.sub.2 Ph                                259  oxazol-2-ylamino                                                                           3     0   H    NHSO.sub.2 -nBu                              260  oxazol-2-ylamino                                                                           3     1   H    NHCbz                                        261  oxazol-2-ylamino                                                                           3     1   H    NHCO.sub.2 -n-Bu                             262  oxazol-2-ylamino                                                                           3     1   H    NHSO.sub.2 Ph                                263  oxazol-2-ylamino                                                                           3     1   H    NHSO.sub.2 -nBu                              264  oxazol-2-ylamino                                                                           4     0   H    NHCbz                                        265  oxazol-2-ylamino                                                                           4     0   H    NHCO.sub.2 -n-Bu                             266  oxazol-2-ylamino                                                                           4     0   H    NHSO.sub.2 Ph                                267  oxazol-2-ylamino                                                                           4     0   H    NHSO.sub.2 -nBu                              268  oxazol-2-ylamino                                                                           3     0   H    NHCbz                                        269  oxazol-2-ylamino                                                                           3     0   H    NHCO.sub.2 -n-Bu                             270  oxazol-2-ylamino                                                                           3     0   H    NHSO.sub.2 Ph                                271  oxazol-2-ylamino                                                                           3     0   H    NHSO.sub.2 -nBu                              272  1,2,5-thiadiazol-3-                                                                        3     1   H    NHCbz                                             ylamino                                                                  273  1,2,5-thiadiazol-3-                                                                        3     1   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  274  1,2,5-thiadiazol-3-                                                                        3     1   H    NHSO.sub.2 Ph                                     ylamino                                                                  275  1,2,5-thiadiazol-3-                                                                        3     1   H    NHSO.sub.2 -nBu                                   ylamino                                                                  276  1,2,5-thiadiazol-3-                                                                        4     0   H    NHCbz                                             ylamino                                                                  277  1,2,5-thiadiazol-3-                                                                        4     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  278  1,2,5-thiadiazol-3-                                                                        4     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  279  1,2,5-thiadiazol-3-                                                                        4     0   H    NHSO.sub.2 -nBu                                   ylamino                                                                  280  1,2,5-thiadiazol-3-                                                                        3     0   H    NHCbz                                             ylamino                                                                  281  1,2,5-thiadiazol-3-                                                                        3     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  282  1,2,5-thiadiazol-3-                                                                        3     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  283  1,2,5-thiadiazol-3-                                                                        3     0   H    NHSO.sub.2 -nBu                                   ylamino                                                                  284  imidazolin-2-                                                                              2     2   H    NHCbz                                             ylamino                                                                  285  imidazolin-2-                                                                              2     2   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  286  imidazolin-2-                                                                              2     2   H    NHSO.sub.2 Ph                                     ylamino                                                                  287  imidazolin-2-                                                                              2     2   H    NHSO.sub.2 -nBu                                   ylamino                                                                  288  tetrahydropyrimidin-                                                                       2     2   H    NHCbz                                             2-ylamino                                                                289  tetrahydropyrimidin-                                                                       2     2   H    NHCO.sub.2 -n-Bu                                  2-ylamino                                                                290  tetrahydropyrimidin-                                                                       2     2   H    NHSO.sub.2 Ph                                     2-ylamino                                                                291  tetrahydropyrimidin-                                                                       2     2   H    NHSO.sub.2 -nBu                                   2-ylamino                                                                292  benzimidazol-2-                                                                            4     0   H    NHCbz                                             ylamino                                                                  293  benzthiazol-2-                                                                             4     0   H    NHCbz                                             ylamino                                                                  294  1,2-pyrazol-3-                                                                             4     0   H    NHCbz                                             ylamino                                                                  295  1,2,4-triazol-5-                                                                           4     0   H    NHCbz                                             ylamino                                                                  296  imidazol-4-ylamino                                                                         4     0   H    NHCbz                                        297  1,3,4-oxadiazol-2-                                                                         4     0   H    NHCbz                                             ylamino                                                                  298  1,2,4-thiadiazol-5-                                                                        4     0   H    NHCbz                                             ylamino                                                                  299  1,2,4-thiadiazol-3-                                                                        4     0   H    NHCbz                                             ylamino                                                                  300  1,2,5-oxadiazol-3-                                                                         4     0   H    NHCbz                                             ylamino                                                                  301  1,2,4-oxadiazol-5-                                                                         4     0   H    NHCbz                                             ylamino                                                                  302  1,2,4-oxadiazol-3-                                                                         4     0   H    NHCbz                                             ylamino                                                                  303  2-iminopyrrolidin-5-                                                                       3     1   H    NHCbz                                             yl                                                                       304  2-iminopyrrolidin-5-                                                                       3     1   H    NHSO.sub.2 Ph                                     yl                                                                       305  2-iminopyrrolidin-5-                                                                       3     0   H    NHCbz                                             yl                                                                       306  2-iminopyrrolidin-5-                                                                       3     0   H    NHSO.sub.2 Ph                                     yl                                                                       307  2-iminopyrrolidin-5-                                                                       2     1   H    NHCbz                                             yl                                                                       308  2-iminopyrrolidin-5-                                                                       2     1   H    NHSO.sub.2 Ph                                     yl                                                                       309  2-iminopiperidin-6-                                                                        3     1   H    NHCbz                                             yl                                                                       310  2-iminopiperidin-6-                                                                        3     1   H    NHSO.sub.2 Ph                                     yl                                                                       311  2-iminopiperidin-6-                                                                        3     0   H    NHCbz                                             yl                                                                       312  2-iminopiperidin-6-                                                                        3     0   H    NHSO.sub.2 Ph                                     yl                                                                       313  2-iminopiperidin-6-                                                                        2     1   H    NHCbz                                             yl                                                                       314  2-iminopiperidin-6-                                                                        2     1   H    NHSO.sub.2 Ph                                     yl                                                                       315  2-iminoazepin-7-yl                                                                         3     1   H    NHCbz                                        316  2-iminoazepin-7-yl                                                                         3     1   H    NHSO.sub.2 Ph                                317  2-iminoazepin-7-yl                                                                         3     0   H    NHCbz                                        318  2-iminoazepin-7-yl                                                                         3     0   H    NHSO.sub.2 Ph                                319  2-iminoazepin-7-yl                                                                         2     1   H    NHCbz                                        320  2-iminoazepin-7-yl                                                                         2     1   H    NHSO.sub.2 Ph                                321  imidazolin-2-                                                                              4     0   H    NHCbz      491                                    ylamino                                                                  322  benzthiazol-2-                                                                             4     0   n-Bu H                                                 ylamino                                                                  323  1,2-pyrazol-3-                                                                             4     0   n-Bu H                                                 ylamino                                                                  324  1,2,4-triazol-5-                                                                           4     0   n-Bu H                                                 ylamino                                                                  325  imidazol-4-ylamino                                                                         4     0   n-Bu H                                            326  1,3,4-oxadiazol-2-                                                                         4     0   n-Bu H                                                 ylamino                                                                  327  imidazolin-2-                                                                              4     0   H    (2,4,6-trimethyl-                                                                        538                                    ylamino                     phenylsulfonyl)-                                                              amino                                        328  1,2,4-thiadiazol-3-                                                                        4     0   n-Bu H                                                 ylamino                                                                  329  1,2,5-oxadiazol-3-                                                                         4     0   n-Bu H                                                 ylamino                                                                  330  imidazolin-2-                                                                              4     0   H    (1-naphthalene-                                                                          546                                    ylamino                     sulphonylamino                               331  1,2,4-oxadiazol-3-                                                                         4     0   n-Bu H                                                 ylamino                                                                  ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                         ##STR19##                                                                    Ex.                                                                           No.  R.sup.1 -U   m     n   R.sup.8                                                                            R.sup.16   MS                                ______________________________________                                        501  tetrahydropyrimidin-                                                                       3     1   H    H                                                 2-ylamino                                                                502  tetrahydropyrimidin-                                                                       3     1   H    NHCbz                                             2-ylamino                                                                503  tetrahydropyrimidin-                                                                       3     1   H    NHtBOC                                            2-ylamino                                                                504  tetrahydropyrimidin-                                                                       3     1   H    NHCO.sub.2 -nBu                                   2-ylamino                                                                505  tetrahydropyrimidin-                                                                       3     1   H    NHCO.sub.2 Et                                     2-ylamino                                                                506  tetrahydropyrimidin-                                                                       3     1   H    NHCO.sub.2 Me                                     2-ylamino                                                                507  tetrahydropyrimidin-                                                                       3     1   H    NHCO(CH.sub.2).sub.n Ph                           2-ylamino                                                                508  tetrahydropyrimidin-                                                                       3     1   H    NHCOtBu                                           2-ylamino                                                                509  tetrahydropyrimidin-                                                                       3     1   H    NHCO-n-C.sub.5 H.sub.11                           2-ylamino                                                                510  tetrahydropyrimidin-                                                                       3     1   H    NHCO-n-C.sub.4 H.sub.9                            2-ylamino                                                                511  tetrahydropyrimidin-                                                                       3     1   H    NHCOCH.sub.2 CH.sub.3                             2-ylamino                                                                512  tetrahydropyrimidin-                                                                       3     1   H    NHCOCH.sub.3                                      2-ylamino                                                                513  tetrahydropyrimidin-                                                                       3     1   H    NHSO.sub.2 CH.sub.3                               2-ylamino                                                                514  tetrahydropyrimidin-                                                                       3     1   H    NHSO.sub.2 CH.sub.2 CH.sub.3                      2-ylamino                                                                515  tetrahydropyrimidin-                                                                       3     1   H    NHSO.sub.2 n-Bu                                   2-ylamino                                                                516  tetrahydropyrimidin-                                                                       3     1   H    NHSO.sub.2 Ph                                     2-ylamino                                                                517  tetrahydropyrimidin-                                                                       3     1   H    NHSO.sub.2 C.sub.6 H.sub.4                        2-ylamino                   (4-CH.sub.3)                                 518  tetrahydropyrimidin-                                                                       3     1   H    NHSO.sub.2 Bn                                     2-ylamino                                                                519  tetrahydropyrimidin-                                                                       3     1   H    NHCO (2-pyridyl)                                  2-ylamino                                                                520  tetrahydropyrimidin-                                                                       3     1   H    NHCO (3-pyridyl)                                  2-ylamino                                                                521  tetrahydropyrimidin-                                                                       3     1   H    NHCO (4-pyridyl)                                  2-ylamino                                                                522  tetrahydropyrimidin-                                                                       3     1   H    NHCOCH.sub.2                                      2-ylamino                   (2-pyridyl)                                  523  tetrahydropyrimidin-                                                                       3     1   H    NHCOCH.sub.2                                      2-ylamino                   (3-pyridyl)                                  524  tetrahydropyrimidin-                                                                       3     1   H    NHCOCH.sub.2                                      2-ylamino                   (4-pyridyl)                                  525  tetrahydropyrimidin-                                                                       3     1   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (2-pyridyl)                                  526  tetrahydropyrimidin-                                                                       3     1   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (3-pyridyl)                                  527  tetrahydropyrimidin-                                                                       3     1   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (4-pyridyl)                                  528  imidazolin-2-                                                                              3     1   H    H                                                 ylamino                                                                  529  imidazolin-2-                                                                              3     1   H    NHCbz                                             ylamino                                                                  530  imidazolin-2-                                                                              3     1   H    NHtBOC                                            ylamino                                                                  531  imidazolin-2-                                                                              3     1   H    NHCO.sub.2 -nBu                                   ylamino                                                                  532  imidazolin-2-                                                                              3     1   H    NHCO.sub.2 Et                                     ylamino                                                                  533  imidazolin-2-                                                                              3     1   H    NHCO.sub.2 Me                                     ylamino                                                                  534  imidazolin-2-                                                                              3     1   H    NHCO(CH.sub.2).sub.n Ph                           ylamino                                                                  535  imidazolin-2-                                                                              3     1   H    NHCOtBu                                           ylamino                                                                  536  imidazolin-2-                                                                              3     1   H    NHCO-n-C.sub.5 H.sub.11                           ylamino                                                                  537  imidazolin-2-                                                                              3     1   H    NHCO-n-C.sub.4 H.sub.9                            ylamino                                                                  538  imidazolin-2-                                                                              3     1   H    NHCOCH.sub.2 CH.sub.3                             ylamino                                                                  539  imidazolin-2-                                                                              3     1   H    NHCOCH.sub.3                                      ylamino                                                                  540  imidazolin-2-                                                                              3     1   H    NHSO.sub.2 CH.sub.3                               ylamino                                                                  541  imidazolin-2-                                                                              3     1   H    NHSO.sub.2 CH.sub.2 CH.sub.3                      ylamino                                                                  542  imidazolin-2-                                                                              3     1   H    NHSO.sub.2 n-Bu                                   ylamino                                                                  543  imidazolin-2-                                                                              3     1   H    NHSO.sub.2 Ph                                     ylamino                                                                  544  imidazolin-2-                                                                              3     1   H    NHSO.sub.2 C.sub.6 H.sub.4                        ylamino                     (4-CH.sub.3)                                 545  imidazolin-2-                                                                              3     1   H    NHSO.sub.2 Bn                                     ylamino                                                                  546  imidazolin-2-                                                                              3     1   H    NHCO (2-pyridyl)                                  ylamino                                                                  547  imidazolin-2-                                                                              3     1   H    NHCO (3-pyridyl)                                  ylamino                                                                  548  imidazolin-2-                                                                              3     1   H    NHCO (4-pyridyl)                                  ylamino                                                                  549  imidazolin-2-                                                                              3     1   H    NHCOCH.sub.2                                      ylamino                     (2-pyridyl)                                  550  imidazolin-2-                                                                              3     1   H    NHCOCH.sub.2                                      ylamino                     (3-pyridyl)                                  551  imidazolin-2-                                                                              3     1   H    NHCOCH.sub.2                                      ylamino                     (4-pyridyl)                                  552  imidazolin-2-                                                                              3     1   H    NHCO.sub.2 CH.sub.2                               ylamino                     (2-pyridyl)                                  553  imidazolin-2-                                                                              3     1   H    NHCO.sub.2 CH.sub.2                               ylamino                     (3-pyridyl)                                  554  imidazolin-2-                                                                              3     1   H    NHCO.sub.2 CH.sub.2                               ylamino                     (4-pyridyl)                                  555  tetrahydropyrimidin-                                                                       4     0   H    H                                                 2-ylamino                                                                556  tetrahydropyrimidin-                                                                       4     0   H    NHCbz                                             2-ylamino                                                                557  tetrahydropyrimidin-                                                                       4     0   H    NHtBOC                                            2-ylamino                                                                558  tetrahydropyrimidin-                                                                       4     0   H    NHCO.sub.2 -nBu                                   2-ylamino                                                                559  tetrahydropyrimidin-                                                                       4     0   H    NHCO.sub.2 Et                                     2-ylamino                                                                560  tetrahydropyrimidin-                                                                       4     0   H    NHCO.sub.2 Me                                     2-ylamino                                                                561  tetrahydropyrimidin-                                                                       4     0   H    NHCO(CH.sub.2).sub.n Ph                           2-ylamino                                                                562  tetrahydropyrimidin-                                                                       4     0   H    NHCOtBu                                           2-ylamino                                                                563  tetrahydropyrimidin-                                                                       4     0   H    NHCO-n-C.sub.5 H.sub.11                           2-ylamino                                                                564  tetrahydropyrimidin-                                                                       4     0   H    NHCO-n-C.sub.4 H.sub.9                            2-ylamino                                                                565  tetrahydropyrimidin-                                                                       4     0   H    NHCOCH.sub.2 CH.sub.3                             2-ylamino                                                                566  tetrahydropyrimidin-                                                                       4     0   H    NHCOCH.sub.3                                      2-ylamino                                                                567  tetrahydropyrimidin-                                                                       4     0   H    NHSO.sub.2 CH.sub.3                               2-ylamino                                                                568  tetrahydropyrimidin-                                                                       4     0   H    NHSO.sub.2 CH.sub.2 CH.sub.3                      2-ylamino                                                                569  tetrahydropyrimidin-                                                                       4     0   H    NHSO.sub.2 n-Bu                                   2-ylamino                                                                570  tetrahydropyrimidin-                                                                       4     0   H    NHSO.sub.2 Ph                                     2-ylamino                                                                571  tetrahydropyrimidin-                                                                       4     0   H    NHSO.sub.2 C.sub.6 H.sub.4                        2-ylamino                   (4-CH.sub.3)                                 572  tetrahydropyrimidin-                                                                       4     0   H    NHSO.sub.2 Bn                                     2-ylamino                                                                573  tetrahydropyrimidin-                                                                       4     0   H    NHCO (2-pyridyl)                                  2-ylamino                                                                574  tetrahydropyrimidin-                                                                       4     0   H    NHCO (3-pyridyl)                                  2-ylamino                                                                575  tetrahydropyrimidin-                                                                       4     0   H    NHCO (4-pyridyl)                                  2-ylamino                                                                576  tetrahydropyrimidin-                                                                       4     0   H    NHCOCH.sub.2                                      2-ylamino                   (2-pyridyl)                                  577  tetrahydropyrimidin-                                                                       4     0   H    NHCOCH.sub.2                                      2-ylamino                   (3-pyridyl)                                  578  tetrahydropyrimidin-                                                                       4     0   H    NHCOCH.sub.2                                      2-ylamino                   (4-pyridyl)                                  579  tetrahydropyrimidin-                                                                       4     0   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (2-pyridyl)                                  580  tetrahydropyrimidin-                                                                       4     0   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (3-pyridyl)                                  581  tetrahydropyrimidin-                                                                       4     0   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (4-pyridyl)                                  582  imidazolin-2-                                                                              4     0   H    H                                                 ylamino                                                                  583  imidazolin-2-                                                                              4     0   H    NHCbz                                             ylamino                                                                  584  imidazolin-2-                                                                              4     0   H    NHtBOC                                            ylamino                                                                  585  imidazolin-2-                                                                              4     0   H    NHCO.sub.2 -nBu                                   ylamino                                                                  586  imidazolin-2-                                                                              4     0   H    NHCO.sub.2 Et                                     ylamino                                                                  587  imidazolin-2-                                                                              4     0   H    NHCO.sub.2 Me                                     ylamino                                                                  588  imidazolin-2-                                                                              4     0   H    NHCO(CH.sub.2).sub.n Ph                           ylamino                                                                  589  imidazolin-2-                                                                              4     0   H    NHCOtBu                                           ylamino                                                                  590  imidazolin-2-                                                                              4     0   H    NHCO-n-C.sub.5 H.sub.11                           ylamino                                                                  591  imidazolin-2-                                                                              4     0   H    NHCO-n-C.sub.4 H.sub.9                            ylamino                                                                  592  imidazolin-2-                                                                              4     0   H    NHCOCH.sub.2 CH.sub.3                             ylamino                                                                  593  imidazolin-2-                                                                              4     0   H    NHCOCH.sub.3                                      ylamino                                                                  594  imidazolin-2-                                                                              4     0   H    NHSO.sub.2 CH.sub.3                               ylamino                                                                  595  imidazolin-2-                                                                              4     0   H    NHSO.sub.2 CH.sub.2 CH.sub.3                      ylamino                                                                  596  imidazolin-2-                                                                              4     0   H    NHSO.sub.2 n-Bu                                   ylamino                                                                  597  imidazolin-2-                                                                              4     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  598  imidazolin-2-                                                                              4     0   H    NHSO.sub.2 C.sub.6 H.sub.4                        ylamino                     (4-CH.sub.3)                                 599  imidazolin-2-                                                                              4     0   H    NHSO.sub.2 Bn                                     ylamino                                                                  600  imidazolin-2-                                                                              4     0   H    NHCO (2-pyridyl)                                  ylamino                                                                  601  imidazolin-2-                                                                              4     0   H    NHCO (3-pyridyl)                                  ylamino                                                                  602  imidazolin-2-                                                                              4     0   H    NHCO (4-pyridyl)                                  ylamino                                                                  603  imidazolin-2-                                                                              4     0   H    NHCOCH.sub.2                                      ylamino                     (2-pyridyl)                                  604  imidazolin-2-                                                                              4     0   H    NHCOCH.sub.2                                      ylamino                     (3-pyridyl)                                  605  imidazolin-2-                                                                              4     0   H    NHCOCH.sub.2                                      ylamino                     (4-pyridyl)                                  606  imidazolin-2-                                                                              4     0   H    NHCO.sub.2 CH.sub.2                               ylamino                     (2-pyridyl)                                  607  imidazolin-2-                                                                              4     0   H    NHCO.sub.2 CH.sub.2                               ylamino                     (3-pyridyl)                                  608  imidazolin-2-                                                                              4     0   H    NHCO.sub.2 CH.sub.2                               ylamino                     (4-pyridyl)                                  609  tetrahydropyrimidin-                                                                       3     0   H    H                                                 2-ylamino                                                                610  tetrahydropyrimidin-                                                                       3     0   H    NHCbz                                             2-ylamino                                                                611  tetrahydropyrimidin-                                                                       3     0   H    NHtBOC                                            2-ylamino                                                                612  tetrahydropyrimidin-                                                                       3     0   H    NHCO.sub.2 -nBu                                   2-ylamino                                                                613  tetrahydropyrimidin-                                                                       3     0   H    NHCO.sub.2 Et                                     2-ylamino                                                                614  tetrahydropyrimidin-                                                                       3     0   H    NHCO.sub.2 Me                                     2-ylamino                                                                615  tetrahydropyrimidin-                                                                       3     0   H    NHCO(CH.sub.2).sub.n Ph                           2-ylamino                                                                616  tetrahydropyrimidin-                                                                       3     0   H    NHCOtBu                                           2-ylamino                                                                617  tetrahydropyrimidin-                                                                       3     0   H    NHCO-n-C.sub.5 H.sub.11                           2-ylamino                                                                618  tetrahydropyrimidin-                                                                       3     0   H    NHCO-n-C.sub.4 H.sub.9                            2-ylamino                                                                619  tetrahydropyrimidin-                                                                       3     0   H    NHCOCH.sub.2 CH.sub.3                             2-ylamino                                                                620  tetrahydropyrimidin-                                                                       3     0   H    NHCOCH.sub.3                                      2-ylamino                                                                621  tetrahydropyrimidin-                                                                       3     0   H    NHSO.sub.2 CH.sub.3                               2-ylamino                                                                622  tetrahydropyrimidin-                                                                       3     0   H    NHSO.sub.2 CH.sub.2 CH.sub.3                      2-ylamino                                                                623  tetrahydropyrimidin-                                                                       3     0   H    NHSO.sub.2 n-Bu                                   2-ylamino                                                                624  tetrahydropyrimidin-                                                                       3     0   H    NHSO.sub.2 Ph                                     2-ylamino                                                                625  tetrahydropyrimidin-                                                                       3     0   H    NHSO.sub.2 C.sub.6 H.sub.4                        2-ylamino                   (4-CH.sub.3)                                 626  tetrahydropyrimidin-                                                                       3     0   H    NHSO.sub.2 Bn                                     2-ylamino                                                                627  tetrahydropyrimidin-                                                                       3     0   H    NHCO (2-pyridyl)                                  2-ylamino                                                                628  tetrahydropyrimidin-                                                                       3     0   H    NHCO (3-pyridyl)                                  2-ylamino                                                                629  tetrahydropyrimidin-                                                                       3     0   H    NHCO (4-pyridyl)                                  2-ylamino                                                                630  tetrahydropyrimidin-                                                                       3     0   H    NHCOCH.sub.2                                      2-ylamino                   (2-pyridyl)                                  631  tetrahydropyrimidin-                                                                       3     0   H    NHCOCH.sub.2                                      2-ylamino                   (3-pyridyl)                                  632  tetrahydropyrimidin-                                                                       3     0   H    NHCOCH.sub.2                                      2-ylamino                   (4-pyridyl)                                  633  tetrahydropyrimidin-                                                                       3     0   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (2-pyridyl)                                  634  tetrahydropyrimidin-                                                                       3     0   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (3-pyridyl)                                  635  tetrahydropyrimidin-                                                                       3     0   H    NHCO.sub.2 CH.sub.2                               2-ylamino                   (4-pyridyl)                                  636  imidazolin-2-                                                                              3     0   H    H                                                 ylamino                                                                  637  imidazolin-2-                                                                              3     0   H    NHCbz                                             ylamino                                                                  638  imidazolin-2-                                                                              3     0   H    NHtBOC                                            ylamino                                                                  639  imidazolin-2-                                                                              3     0   H    NHCO.sub.2 -nBu                                   ylamino                                                                  640  imidazolin-2-                                                                              3     0   H    NHCO.sub.2 Et                                     ylamino                                                                  641  imidazolin-2-                                                                              3     0   H    NHCO.sub.2 Me                                     ylamino                                                                  642  imidazolin-2-                                                                              3     0   H    NHCO(CH.sub.2).sub.n Ph                           ylamino                                                                  643  imidazolin-2-                                                                              3     0   H    NHCOtBu                                           ylamino                                                                  644  imidazolin-2-                                                                              3     0   H    NHCO-n-C.sub.5 H.sub.11                           ylamino                                                                  645  imidazolin-2-                                                                              3     0   H    NHCO-n-C.sub.4 H.sub.9                            ylamino                                                                  646  imidazolin-2-                                                                              3     0   H    NHCOCH.sub.2 CH.sub.3                             ylamino                                                                  647  imidazolin-2-                                                                              3     0   H    NHCOCH.sub.3                                      ylamino                                                                  648  imidazolin-2-                                                                              3     0   H    NHSO.sub.2 CH.sub.3                               ylamino                                                                  649  imidazolin-2-                                                                              3     0   H    NHSO.sub.2 CH.sub.2 CH.sub.3                      ylamino                                                                  650  imidazolin-2-                                                                              3     0   H    NHSO.sub.2 n-Bu                                   ylamino                                                                  651  imidazolin-2-                                                                              3     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  652  imidazolin-2-                                                                              3     0   H    NHSO.sub.2 C.sub.6 H.sub.4                        ylamino                     (4-CH.sub.3)                                 653  imidazolin-2-                                                                              3     0   H    NHSO.sub.2 Bn                                     ylamino                                                                  654  imidazolin-2-                                                                              3     0   H    NHCO (2-pyridyl)                                  ylamino                                                                  655  imidazolin-2-                                                                              3     0   H    NHCO (3-pyridyl)                                  ylamino                                                                  656  imidazolin-2-                                                                              3     0   H    NHCO (4-pyridyl)                                  ylamino                                                                  657  imidazolin-2-                                                                              3     0   H    NHCOCH.sub.2                                      ylamino                     (2-pyridyl)                                  658  imidazolin-2-                                                                              3     0   H    NHCOCH.sub.2                                      ylamino                     (3-pyridyl)                                  659  imidazolin-2-                                                                              3     0   H    NHCOCH.sub.2                                      ylamino                     (4-pyridyl)                                  660  imidazolin-2-                                                                              3     0   H    NHCO.sub.2 CH.sub.2                               ylamino                     (2-pyridyl)                                  661  imidazolin-2-                                                                              3     0   H    NHCO.sub.2 CH.sub.2                               ylamino                     (3-pyridyl)                                  662  imidazolin-2-                                                                              3     0   H    NHCO.sub.2 CH.sub.2                               ylamino                     (4-pyridyl)                                  663  pyridin-2-ylamino                                                                          3     1   H    NHCbz                                        664  pyridin-2-ylamino                                                                          3     1   H    NHCO.sub.2 -n-Bu                             665  pyridin-2-ylamino                                                                          3     1   H    NHSO.sub.2 Ph                                666  pyridin-2-ylamino                                                                          3     1   H    NHSO.sub.2 -nBu                              667  pyridin-2-ylamino                                                                          4     0   H    NHCbz                                        668  pyridin-2-ylamino                                                                          4     0   H    NHCO.sub.2 -n-Bu                             669  pyridin-2-ylamino                                                                          4     0   H    NHSO.sub.2 Ph                                670  pyridin-2-ylamino                                                                          4     0   H    NHSO.sub.2 -nBu                              671  pyridin-2-ylamino                                                                          3     0   H    NHCbz                                        672  pyridin-2-ylamino                                                                          3     0   H    NHCO.sub.2 -n-Bu                             673  pyridin-2-ylamino                                                                          3     0   H    NHSO.sub.2 Ph                                674  pyridin-2-ylamino                                                                          3     0   H    NHSO.sub.2 -nBu                              675  imidazol-2-ylamino                                                                         3     1   H    NHCbz                                        676  imidazol-2-ylamino                                                                         3     1   H    NHCO.sub.2 -n-Bu                             677  imidazol-2-ylamino                                                                         3     1   H    NHSO.sub.2 Ph                                678  imidazol-2-ylamino                                                                         3     1   H    NHSO.sub.2 -nBu                              679  imidazol-2-ylamino                                                                         4     0   H    NHCbz                                        680  imidazol-2-ylamino                                                                         4     0   H    NHCO.sub.2 -n-Bu                             681  imidazol-2-ylamino                                                                         4     0   H    NHSO.sub.2 Ph                                682  imidazol-2-ylamino                                                                         4     0   H    NHSO.sub.2 -nBu                              683  imidazol-2-ylamino                                                                         3     0   H    NHCbz                                        684  imidazol-2-ylamino                                                                         3     0   H    NHCO.sub.2 -n-Bu                             685  imidazol-2-ylamino                                                                         3     0   H    NHSO.sub.2 Ph                                686  imidazol-2-ylamino                                                                         3     0   H    NHSO.sub.2 -nBu                              687  thiazol-2-ylamino                                                                          3     1   H    NHCbz                                        688  2-aminopyridin-6-yl                                                                        3     1   H    NHCO.sub.2 -n-Bu                             689  2-aminopyridin-6-yl                                                                        3     1   H    NHSO.sub.2 Ph                                690  2-aminopyridin-6-yl                                                                        3     1   H    NHSO.sub.2 -nBu                              691  2-aminopyridin-6-yl                                                                        4     0   H    NHCbz                                        692  2-aminopyridin-6-yl                                                                        4     0   H    NHCO.sub.2 -n-Bu                             693  2-aminopyridin-6-yl                                                                        4     0   H    NHSO.sub.2 Ph                                694  2-aminopyridin-6-yl                                                                        4     0   H    NHSO.sub.2 -nBu                              695  2-aminopyridin-6-yl                                                                        3     0   H    NHCbz                                        696  2-aminopyridin-6-yl                                                                        3     0   H    NHCO.sub.2 -n-Bu                             697  2-aminopyridin-6-yl                                                                        3     0   H    NHSO.sub.2 Ph                                698  2-aminopyridin-6-yl                                                                        3     0   H    NHSO.sub.2 -nBu                              699  2-aminopyridin-3-yl                                                                        2     0   H    NHCbz                                        700  2-aminopyridin-3-yl                                                                        2     0   H    NHCO.sub.2 -n-Bu                             701  2-aminopyridin-3-yl                                                                        2     0   H    NHSO.sub.2 Ph                                702  2-aminopyridin-3-yl                                                                        2     0   H    NHSO.sub.2 -nBu                              703  2-aminothiazol-4-yl                                                                        3     1   H    NHCbz                                        704  2-aminothiazol-4-yl                                                                        3     1   H    NHCO.sub.2 -n-Bu                             705  2-aminothiazol-4-yl                                                                        3     1   H    NHSO.sub.2 Ph                                706  2-aminothiazol-4-yl                                                                        3     1   H    NHSO.sub.2 -nBu                              707  2-aminothiazol-4-yl                                                                        4     0   H    NHCbz                                        708  2-aminothiazol-4-yl                                                                        4     0   H    NHCO.sub.2 -n-Bu                             709  2-aminothiazol-4-yl                                                                        4     0   H    NHSO.sub.2 Ph                                710  2-aminopyridin-6-yl                                                                        4     0   H    NHSO.sub.2 -nBu                              711  2-aminothiazol-4-yl                                                                        3     0   H    NHCbz                                        712  2-aminothiazol-4-yl                                                                        3     0   H    NHCO.sub.2 -n-Bu                             713  2-aminothiazol-4-yl                                                                        3     0   H    NHSO.sub.2 Ph                                714  2-aminothiazol-4-yl                                                                        3     0   H    NHSO.sub.2 -nBu                              715  2-aminothiazol-4-yl                                                                        3     1   H    NHCbz                                        716  2-aminothiazol-4-yl                                                                        3     1   H    NHCO.sub.2 -n-Bu                             717  1,3,4-thiadiazol-2-                                                                        3     1   H    NHSO.sub.2 Ph                                     ylamino                                                                  718  1,3,4-thiadiazol-2-                                                                        3     1   H    NHSO.sub.2 -nBu                                   ylamino                                                                  719  1,3,4-thiadiazol-2-                                                                        4     0   H    NHCbz                                             ylamino                                                                  720  1,3,4-thiadiazol-2-                                                                        4     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  721  1,3,4-thiadiazol-2-                                                                        4     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  722  1,3,4-thiadiazol-2-                                                                        4     0   H    NHSO.sub.2 -nBu                                   ylamino                                                                  723  1,3,4-thiadiazol-2-                                                                        3     0   H    NHCbz                                             ylamino                                                                  724  1,3,4-thiadiazol-2-                                                                        3     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  725  1,3,4-thiadiazol-2-                                                                        3     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  726  1,2,4-thiadiazol-5-                                                                        3     0   H    NHSO.sub.2 -nBu                                   ylamino                                                                  727  1,2,4-thiadiazol-5-                                                                        3     1   H    NHCbz                                             ylamino                                                                  728  1,2,4-thiadiazol-5-                                                                        3     1   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  729  1,2,4-thiadiazol-5-                                                                        3     1   H    NHSO.sub.2 Ph                                     ylamino                                                                  730  1,2,4-thiadiazol-5-                                                                        3     1   H    NHSO.sub.2 -nBu                                   ylamino                                                                  731  1,2,4-thiadiazol-5-                                                                        4     0   H    NHCbz                                             ylamino                                                                  732  1,2,4-thiadiazol-5-                                                                        4     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  733  1,2,4-thiadiazol-5-                                                                        4     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  734  1,2,4-thiadiazol-5-                                                                        4     0   H    NHSO.sub.2 -nBu                                   ylamino                                                                  735  1,2,4-thiadiazol-5-                                                                        3     0   H    NHCbz                                             ylamino                                                                  736  1,2,4-thiadiazol-5-                                                                        3     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  737  1,2,4-thiadiazol-5-                                                                        3     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  738  isoxazol-3-ylamino                                                                         3     0   H    NHSO.sub.2 -nBu                              739  isoxazol-3-ylamino                                                                         3     1   H    NHCbz                                        740  isoxazol-3-ylamino                                                                         3     1   H    NHCO.sub.2 -n-Bu                             741  isoxazol-3-ylamino                                                                         3     1   H    NHSO.sub.2 Ph                                742  isoxazol-3-ylamino                                                                         3     1   H    NHSO.sub.2 -nBu                              743  isoxazol-3-ylamino                                                                         4     0   H    NHCbz                                        744  isoxazol-3-ylamino                                                                         4     0   H    NHCO.sub.2 -n-Bu                             745  isoxazol-3-ylamino                                                                         4     0   H    NHSO.sub.2 Ph                                746  isoxazol-3-ylamino                                                                         4     0   H    NHSO.sub.2 -nBu                              747  isoxazol-3-ylamino                                                                         3     0   H    NHCbz                                        748  isoxazol-3-ylamino                                                                         3     0   H    NHCO.sub.2 -n-Bu                             749  isoxazol-3-ylamino                                                                         3     0   H    NHSO.sub.2 Ph                                750  oxazol-2-ylamino                                                                           3     0   H    NHSO.sub.2 -nBu                              751  oxazol-2-ylamino                                                                           3     1   H    NHCbz                                        752  oxazol-2-ylamino                                                                           3     1   H    NHCO.sub.2 -n-Bu                             753  oxazol-2-ylamino                                                                           3     1   H    NHSO.sub.2 Ph                                754  oxazol-2-ylamino                                                                           3     1   H    NHSO.sub.2 -nBu                              755  oxazol-2-ylamino                                                                           4     0   H    NHCbz                                        756  oxazol-2-ylamino                                                                           4     0   H    NHCO.sub.2 -n-Bu                             757  oxazol-2-ylamino                                                                           4     0   H    NHSO.sub.2 Ph                                758  oxazol-2-ylamino                                                                           4     0   H    NHSO.sub.2 -nBu                              759  oxazol-2-ylamino                                                                           3     0   H    NHCbz                                        760  oxazol-2-ylamino                                                                           3     0   H    NHCO.sub.2 -n-Bu                             761  oxazol-2-ylamino                                                                           3     0   H    NHSO.sub.2 Ph                                762  oxazol-2-ylamino                                                                           3     0   H    NHSO.sub.2 -nBu                              763  1,2,5-thiadiazol-3-                                                                        3     1   H    NHCbz                                             ylamino                                                                  764  1,2,5-thiadiazol-3-                                                                        3     1   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  765  1,2,5-thiadiazol-3-                                                                        3     1   H    NHSO.sub.2 Ph                                     ylamino                                                                  766  1,2,5-thiadiazol-3-                                                                        3     1   H    NHSO.sub.2 -nBu                                   ylamino                                                                  767  1,2,5-thiadiazol-3-                                                                        4     0   H    NHCbz                                             ylamino                                                                  768  1,2,5-thiadiazol-3-                                                                        4     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  769  1,2,5-thiadiazol-3-                                                                        4     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  770  1,2,5-thiadiazol-3-                                                                        4     0   H    NHSO.sub.2 -nBu                                   ylamino                                                                  771  1,2,5-thiadiazol-3-                                                                        3     0   H    NHCbz                                             ylamino                                                                  772  1,2,5-thiadiazol-3-                                                                        3     0   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  773  1,2,5-thiadiazol-3-                                                                        3     0   H    NHSO.sub.2 Ph                                     ylamino                                                                  774  1,2,5-thiadiazol-3-                                                                        3     0   H    NHSO.sub.2 -nBu                                   ylamino                                                                  775  imidazolin-2-                                                                              2     2   H    NHCbz                                             ylamino                                                                  776  imidazolin-2-                                                                              2     2   H    NHCO.sub.2 -n-Bu                                  ylamino                                                                  777  imidazolin-2-                                                                              2     2   H    NHSO.sub.2 Ph                                     ylamino                                                                  778  imidazolin-2-                                                                              2     2   H    NHSO.sub.2 -nBu                                   ylamino                                                                  779  tetrahydropyrimidin-                                                                       2     2   H    NHCbz                                             2-ylamino                                                                780  tetrahydropyrimidin-                                                                       2     2   H    NHCO.sub.2 -n-Bu                                  2-ylamino                                                                781  tetrahydropyrimidin-                                                                       2     2   H    NHSO.sub.2 Ph                                     2-ylamino                                                                782  tetrahydropyrimidin-                                                                       2     2   H    NHSO.sub.2 -nBu                                   2-ylamino                                                                783  benzimidazol-2-                                                                            4     0   H    NHCbz                                             ylamino                                                                  784  benzthiazol-2-                                                                             4     0   H    NHCbz                                             ylamino                                                                  785  1,2-pyrazol-3-                                                                             4     0   H    NHCbz                                             ylamino                                                                  786  1,2,4-triazol-5-                                                                           4     0   H    NHCbz                                             ylamino                                                                  787  imidazol-4-ylamino                                                                         4     0   H    NHCbz                                        788  1,3,4-oxadiazol-2-                                                                         4     0   H    NHCbz                                             ylamino                                                                  789  1,2,4-thiadiazol-5-                                                                        4     0   H    NHCbz                                             ylamino                                                                  790  1,2,4-thiadiazol-3-                                                                        4     0   H    NHCbz                                             ylamino                                                                  791  1,2,5-oxadiazol-3-                                                                         4     0   H    NHCbz                                             ylamino                                                                  792  1,2,4-oxadiazol-5-                                                                         4     0   H    NHCbz                                             ylamino                                                                  793  1,2,4-oxadiazol-3-                                                                         4     0   H    NHCbz                                             ylamino                                                                  794  2-iminopyrrolidin-                                                                         3     1   H    NHCbz                                             5-yl                                                                     795  2-iminopyrrolidin-                                                                         3     1   H    NHSO.sub.2 Ph                                     5-yl                                                                     796  2-iminopyrrolidin-                                                                         3     0   H    NHCbz                                             5-yl                                                                     797  2-iminopyrrolidin-                                                                         3     0   H    NHSO.sub.2 Ph                                     5-yl                                                                     798  2-iminopyrrolidin-                                                                         2     1   H    NHCbz                                             5-yl                                                                     799  2-iminopyrrolidin-                                                                         2     1.  H    NHSO.sub.2 Ph                                     5-yl                                                                     800  2-iminopiperidin-6-                                                                        3     1   H    NHCbz                                             yl                                                                       801  2-iminopiperidin-6-                                                                        3     1   H    NHSO.sub.2 Ph                                     yl                                                                       802  2-iminopiperidin-6-                                                                        3     0   H    NHCbz                                             yl                                                                       803  2-iminopiperidin-6-                                                                        3     0   H    NHSO.sub.2 Ph                                     yl                                                                       804  2-iminopiperidin-6-                                                                        2     1   H    NHCbz                                             yl                                                                       805  2-iminopiperidin-6-                                                                        2     1   H    NHSO.sub.2 Ph                                     yl                                                                       806  2-iminoazepin-7-yl                                                                         3     1   H    NHCbz                                        807  2-iminoazepin-7-yl                                                                         3     1   H    NHSO.sub.2 Ph                                808  2-iminoazepin-7-yl                                                                         3     0   H    NHCbz                                        809  2-iminoazepin-7-yl                                                                         3     0   H    NHSO.sub.2 Ph                                810  2-iminoazepin-7-yl                                                                         2     1   H    NHCbz                                        811  2-iminoazepin-7-yl                                                                         2     1   H    NHSO.sub.2 Ph                                812  benzimidazol-2-                                                                            4     0   n-Bu H                                                 ylamino                                                                  813  benzthiazol-2-                                                                             4     0   n-Bu H                                                 ylamino                                                                  814  1,2-pyrazol-3-                                                                             4     0   n-Bu H                                                 ylamino                                                                  815  1,2,4-triazol-5-                                                                           4     0   n-Bu H                                                 ylamino                                                                  816  imidazol-4-ylamino                                                                         4     0   n-Bu H                                            817  1,3,4-oxadiazol-2-                                                                         4     0   n-Bu H                                                 ylamino                                                                  818  1,2,4-thiadiazol-5-                                                                        4     0   n-Bu H                                                 ylamino                                                                  819  1,2,4-thiadiazol-3-                                                                        4     0   n-Bu H                                                 ylamino                                                                  820  1,2,5-oxadiazol-3-                                                                         4     0   n-Bu H                                                 ylamino                                                                  821  1,2,4-oxadiazol-5-                                                                         4     0   n-Bu H                                                 ylamino                                                                  822  1,2,4-oxadiazol-3-                                                                         4     0   n-Bu H                                                 ylamino                                                                  ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         ##STR20##                                                                    Ex.                                                                           No.  R.sup.1 -U    m     n   G   R.sup.8                                                                           R.sup.9                                  ______________________________________                                        1001 imidazolin-2-ylamino                                                                        3     0   O   H   H                                        1002 imidazolin-2-ylamino                                                                        2     0   O   H   H                                        1003 imidazolin-2-ylamino                                                                        2     0   O   H   NHCbz                                    1004 imidazolin-2-ylamino                                                                        3     0   O   H   NHCbz                                    1005 imidazolin-2-ylamino                                                                        2     0   S   H   NHCbz                                    1006 imidazolin-2-ylamino                                                                        3     0   S   H   NHCbz                                    1009 tetrahydropyrimidin-                                                                        2     0   O   H   H                                             2-ylamino                                                                1010 tetrahydropyrimidin-                                                                        2     0   O   H   NHCbz                                         2-ylamino                                                                1011 tetrahydropyrimidin-                                                                        3     0   O   H   H                                             2-ylamino                                                                1012 tetrahydropyrimidin-                                                                        3     0   O   H   NHCbz                                         2-ylamino                                                                1013 tetrahydropyrimidin-                                                                        2     0   S   H   NHCbz                                         2-ylamino                                                                1014 tetrahydropyrimidin-                                                                        3     0   S   H   NHCbz                                         2-ylamino                                                                1015 tetrahydropyrimidin-                                                                        2     0   O   H   NHCbz                                         2-ylamino                                                                1017 imidazolin-2-ylamino                                                                        2     0   O   H   NH-n-Bu                                  1018 imidazolin-2-ylamino                                                                        3     0   O   H   NH-n-Bu                                  1019 imidazolin-2-ylamino                                                                        2     0   S   H   NH-n-Bu                                  1020 imidazolin-2-ylamino                                                                        3     0   S   H   NH-n-Bu                                  1023 tetrahydropyrimidin-                                                                        2     0   O   H   NH-n-Bu                                       2-ylamino                                                                1024 tetrahydropyrimidin-                                                                        3     0   O   H   NH-n-Bu                                       2-ylamino                                                                1025 tetrahydropyrimidin-                                                                        2     0   S   H   NH-n-Bu                                       2-ylamino                                                                1026 tetrahydropyrimidin-                                                                        3     0   S   H   NH-n-Bu                                       2-ylamino                                                                1027 tetrahydropyrimidin-                                                                        2     0   S   H   NH-n-Bu                                       2-ylamino                                                                1028 tetrahydropyrimidin-                                                                        3     0   O   H   NH-n-Bu                                       2-ylamino                                                                1029 imidazolin-2-ylamino                                                                        2     0   O   H   NHSO.sub.2 Ph                                                                 (o-CH.sub.3)                             1030 imidazolin-2-ylamino                                                                        3     0   O   H   NHSO.sub.2 Ph                                                                 (o-CH.sub.3)                             1031 imidazolin-2-ylamino                                                                        2     0   S   H   NHSO.sub.2 Ph                                                                 (o-CH.sub.3)                             1032 imidazolin-2-ylamino                                                                        3     0   S   H   NHSO.sub.2 Ph                                                                 (o-CH.sub.3)                             1033 imidazolin-2-ylamino                                                                        2     0   O   H   NHSO.sub.2 Ph                                                                 (m-CH.sub.3)                             1034 imidazolin-2-ylamino                                                                        3     0   O   H   NHSO.sub.2 Ph                                                                 (m-CH.sub.3)                             1035 imidazolin-2-ylamino                                                                        2     0   S   H   NHSO.sub.2 Ph                                                                 (m-CH.sub.3)                             1036 imidazolin-2-ylamino                                                                        3     0   S   H   NHSO.sub.2 Ph                                                                 (m-CH.sub.3)                             1037 imidazolin-2-ylamino                                                                        2     0   O   H   NHSO.sub.2 Ph                                                                 (p-CH.sub.3)                             1038 imidazolin-2-ylamino                                                                        3     0   O   H   NHSO.sub.2 Ph                                                                 (p-CH.sub.3)                             1039 imidazolin-2-ylamino                                                                        2     0   S   H   NHSO.sub.2 Ph                                                                 (p-CH.sub.3)                             1040 imidazolin-2-ylamino                                                                        3     0   S   H   NHSO.sub.2 Ph                                                                 (p-CH.sub.3)                             1041 imidazolin-2-ylamino                                                                        2     0   O   H   SO.sub.2 Ph (o-Cl)                       1042 imidazolin-2-ylamino                                                                        3     0   O   H   SO.sub.2 Ph (o-Cl)                       1043 imidazolin-2-ylamino                                                                        2     0   O   H   SO.sub.2 Ph (m-Cl)                       1044 imidazolin-2-ylamino                                                                        3     0   O   H   SO.sub.2 Ph (m-Cl)                       1045 imidazolin-2-ylamino                                                                        2     0   O   H   SO.sub.2 Ph (p-Cl)                       1046 imidazolin-2-ylamino                                                                        3     0   O   H   SO.sub.2 Ph (p-Cl)                       1047 tetrahydropyrimidin-                                                                        2     0   O   H   SO.sub.2 Ph (p-Cl)                            2-ylamino                                                                1048 tetrahydropyrimidin-                                                                        3     0   O   H   SO.sub.2 Ph (p-Cl)                            2-ylamino                                                                1049 tetrahydropyrimidin-                                                                        2     0   O   H   SO.sub.2 Ph (m-Cl)                            2-ylamino                                                                1050 tetrahydropyrimidin-                                                                        3     0   O   H   SO.sub.2 Ph (m-Cl)                            2-ylamino                                                                1051 tetrahydropyrimidin-                                                                        2     0   O   H   SO.sub.2 Ph (p-Cl)                            2-ylamino                                                                1052 tetrahydropyrimidin-                                                                        3     0   O   H   SO.sub.2 Ph (p-Cl)                            2-ylamino                                                                1053 imidazolin-2-ylamino                                                                        2     0   O   H   NHPh (m-F)                               1054 imidazolin-2-ylamino                                                                        3     0   O   H   NHPh (m-F)                               1055 tetrahydropyrimidin-                                                                        2     0   O   H   NHPh (m-F)                                    2-ylamino                                                                1056 tetrahydropyrimidin-                                                                        3     0   O   H   NHPh (m-F)                                    2-ylamino                                                                1057 imidazolin-2-ylamino                                                                        2     0   O   H   NHPh (p-F)                               1058 imidazolin-2-ylamino                                                                        3     0   O   H   NHPh (p-F)                               1059 tetrahydropyrimidin-                                                                        2     0   O   H   NHPh (p-F)                                    2-ylamino                                                                1060 tetrahydropyrimidin-                                                                        3     0   O   H   NHPh (p-F)                                    2-ylamino                                                                1061 imidazolin-2-ylamino                                                                        2     0   O   H   NHPh (m-Br)                              1062 imidazolin-2-ylamino                                                                        3     0   O   H   NHPh (m-Br)                              1063 tetrahydropyrimidin-                                                                        2     0   O   H   NHPh (m-Br)                                   2-ylamino                                                                1064 tetrahydropyrimidin-                                                                        3     0   O   H   NHPh (m-Br)                                   2-ylamino                                                                1065 imidazolin-2-ylamino                                                                        2     0   O   H   NHSO.sub.2 Ph (p-Br)                     1066 imidazolin-2-ylamino                                                                        3     0   O   H   NHSO.sub.2 Ph (p-Br)                     1067 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 Ph (p-Br)                          2-ylamino                                                                1068 tetrahydropyrimidin-                                                                        3     0   O   H   NHSO.sub.2 Ph (p-Br)                          2-ylamino                                                                1069 imidazolin-2-ylamino                                                                        2     0   O   H   NHSO.sub.2 Ph                                                                 (m-OCH.sub.3)                            1070 imidazolin-2-ylamino                                                                        3     0   O   H   NHSO.sub.2 Ph                                                                 (m-OCH.sub.3)                            1071 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 Ph                                 2-ylamino                       (m-OCH.sub.3)                            1072 tetrahydropyrimidin-                                                                        3     0   O   H   NHSO.sub.2 Ph                                 2-ylamino                       (m-OCH.sub.3)                            1073 imidazolin-2-ylamino                                                                        2     0   O   H   NHSO.sub.2 Ph                                                                 (p-OCH.sub.3)                            1074 imidazolin-2-ylamino                                                                        3     0   O   H   NHSO.sub.2 Ph                                                                 (p-OCH.sub.3)                            1075 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 Ph                                 2-ylamino                       (p-OCH.sub.3)                            1076 tetrahydropyrimidin-                                                                        3     0   O   H   NHSO.sub.2 Ph                                 2-ylamino                       (p-OCH.sub.3)                            1077 imidazolin-2-ylamino                                                                        2     0   O   H   NHSO.sub.2 Bn                            1078 imidazolin-2-ylamino                                                                        3     0   O   H   NHSO.sub.2 Bn                            1079 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 Bn                                 2-ylamino                                                                1080 tetrahydropyrimidin-                                                                        3     0   O   H   NHSO.sub.2 Bn                                 2-ylamino                                                                1081 imidazolin-2-ylamino                                                                        2     0   O   H   NHSO.sub.2 Et                            1082 imidazolin-2-ylamino                                                                        3     0   O   H   NHSO.sub.2 Et                            1083 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 Et                                 2-ylamino                                                                1084 tetrahydropyrimidin-                                                                        3     0   O   H   NHSO.sub.2 Et                                 2-ylamino                                                                ______________________________________                                        Ex.                                                                           No.  R.sup.1 -U    m     n   Q   R.sup.8                                                                           R.sup.9                                  ______________________________________                                        1085 imidazolin-2-ylamino                                                                        2     0   O   H   NHSO.sub.2 -n-Pr                         1086 imidazolin-2-ylamino                                                                        3     0   O   H   NHSO.sub.2 -n-Pr                         1087 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 -n-Pr                              2-ylamino                                                                1088 tetrahydropyrimidin-                                                                        3     0   O   H   NHSO.sub.2 -n-Pr                              2-ylamino                                                                1089 imidazolin-2-ylamino                                                                        2     0   O   H   NHSO.sub.2 -n-                                                                (C.sub.5 H.sub.11)                       1090 imidazolin-2-ylamino                                                                        3     0   O   H   NHSO.sub.2 -n-                                                                (C.sub.5 H.sub.11)                       1091 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 -n-                                2-ylamino                       (C.sub.5 H.sub.11)                       1092 tetrahydropyrimidin-                                                                        3     0   O   H   NHSO.sub.2 -n-                                2-ylamino                       (C.sub.5 H.sub.11)                       1093 imidazolin-2-ylamino                                                                        2     0   O   H   NHCO.sub.2 Et                            1094 imidazolin-2-ylamino                                                                        3     0   O   H   NHCO.sub.2 Et                            1095 tetrahydropyrimidin-                                                                        2     0   O   H   NHCO.sub.2 Et                                 2-ylamino                                                                1096 tetrahydropyrimidin-                                                                        3     0   O   H   NHCO.sub.2 Et                                 2-ylamino                                                                1097 imidazolin-2-ylamino                                                                        2     0   O   H   NHCO.sub.2 -n-C.sub.5 H.sub.11           1098 imidazolin-2-ylamino                                                                        3     0   O   H   NHCO.sub.2 -n-C.sub.5 H.sub.11           1099 tetrahydropyrimidin-                                                                        2     0   O   H   NHCO.sub.2 -n-C.sub.5 H.sub.11                2-ylamino                                                                1100 tetrahydropyrimidin-                                                                        3     0   O   H   NHCO.sub.2 -n-C.sub.5 H.sub.11                2-ylamino                                                                1101 imidazolin-2-ylamino                                                                        4     0   O   H   NHCbz                                    1102 tetrahydropyrimidin-                                                                        4     0   O   H   NHCbz                                         2-ylamino                                                                1103 imidazolin-2-ylamino                                                                        4     0   O   H   NHCO.sub.2 -n-Bu                         1104 tetrahydropyrimidin-                                                                        4     0   O   H   NHCO.sub.2 -n-Bu                              2-ylamino     4     0   O   H   NHSO.sub.2 Ph                            1105 imidazolin-2-ylamino                                                     1106 tetrahydropyrimidin-                                                                        4     0   O   H   NHSO.sub.2 Ph                                 2-ylamino                                                                1107 imidazolin-2-ylamino                                                                        4     0   O   H   NHSO.sub.2 -n-Bu                         1108 tetrahydropyrimidin-                                                                        4     0   O   H   NHSO.sub.2 -n-Bu                              2-ylamino                                                                1109 imidazolin-2-ylamino                                                                        4     0   S   H   NHCbz                                    1110 tetrahydropyrimidin-                                                                        4     0   S   H   NHCbz                                         2-ylamino                                                                1111 imidazolin-2-ylamino                                                                        4     0   S   H   NHSO.sub.2 Bu                            1112 tetrahydropyrimidin-                                                                        4     0   S   H   NHSO.sub.2 Bu                                 2-ylamino                                                                1113 imidazolin-2-ylamino                                                                        2     0   O   Me  H                                        1114 imidazolin-2-ylamino                                                                        3     0   O   Me  H                                        ______________________________________                                        Ex.                                                                           No.  R.sup.1 -U    m     n   G   R.sup.8                                                                           R.sup.9                                  ______________________________________                                        1115 tetrahydropyrimidin-                                                                        2     0   O   Me  H                                             2-ylamino                                                                1116 tetrahydropyrimidin-                                                                        3     0   O   Me  H                                             2-ylamino                                                                1117 imidazolin-2-ylamino                                                                        3     0   S   Me  H                                        1118 tetrahydropyrimidin-                                                                        3     0   S   Me  H                                             2-ylamino                                                                1119 imidazolin-2-ylamino                                                                        2     0   O   Me  NHCbz                                    1120 imidazolin-2-ylamino                                                                        3     0   O   Me  NHCbz                                    1121 tetrahydropyrimidin-                                                                        2     0   O   Me  NHSO.sub.2 -n-Bu                              2-ylamino                                                                1122 tetrahydropyrimidin-                                                                        3     0   O   Me  NHSO.sub.2 -n-Bu                              2-ylamino                                                                1123 imidazolin-2-ylamino                                                                        2     0   O   Et  H                                        1124 imidazolin-2-ylamino                                                                        3     0   O   Et  H                                        1125 tetrahydropyrimidin-                                                                        2     0   O   Et  H                                             2-ylamino                                                                1126 tetrahydropyrimidin-                                                                        3     0   O   Et  H                                             2-ylamino                                                                1127 imidazolin-2-ylamino                                                                        3     0   S   Et  H                                        1128 tetrahydropyrimidin-                                                                        3     0   S   Et  H                                             2-ylamino                                                                1129 imidazolin-2-ylamino                                                                        2     0   O   Ph  H                                        1130 imidazolin-2-ylamino                                                                        3     0   O   Ph  H                                        1131 tetrahydropyrimidin-                                                                        2     0   O   Ph  H                                             2-ylamino                                                                1132 tetrahydropyrimidin-                                                                        3     0   O   Ph  H                                             2-ylamino                                                                1133 imidazolin-2-ylamino                                                                        3     0   S   Ph  H                                        1134 tetrahydropyrimidin-                                                                        3     0   S   Ph  H                                             2-ylamino                                                                1135 imidazolin-2-ylamino                                                                        2     0   O   Bn  H                                        1136 imidazolin-2-ylamino                                                                        3     0   O   Bn  H                                        1137 tetrahydropyrimidin-                                                                        2     0   O   Bn  H                                             2-ylamino                                                                1138 tetrahydropyrimidin-                                                                        3     0   O   Bn  H                                             2-ylamino                                                                1139 imidazolin-2-ylamino                                                                        3     0   S   Bn  H                                        1140 tetrahydropyrimidin-                                                                        3     0   S   Bn  H                                             2-ylamino                                                                1141 imidazolin-2-ylamino                                                                        2     0   O   H   NHCbz                                    1142 imidazolin-2-ylamino                                                                        3     0   O   H   NHCbz                                    1143 tetrahydropyrimidin-                                                                        2     0   O   H   NHCbz                                         2-ylamino                                                                1144 tetrahydropyrimidin-                                                                        3     0   O   H   NHCbz                                         2-ylamino                                                                1145 imidazolin-2-ylamino                                                                        2     0   O   H   NHSO.sub.2 -n-Bu                         1146 imidazolin-2-ylamino                                                                        3     0   O   H   NHSO.sub.2 -n-Bu                         1147 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 -n-Bu                              2-ylamino                                                                1148 tetrahydropyrimidin-                                                                        3     0   O   H   NHSO.sub.2 -n-Bu                              2-ylamino                                                                1149 imidazolin-2-ylamino                                                                        3     0   S   H   NHCbz                                    1150 tetrahydropyrimidin-                                                                        3     0   S   H   NHCbz                                         2-ylamino                                                                1151 imidazolin-2-ylamino                                                                        3     0   S   H   NHSO.sub.2 -n-Bu                         1152 tetrahydropyrimidin-                                                                        3     0   S   H   NHSO.sub.2 -n-Bu                              2-ylamino                                                                1153 imidazolin-2-ylamino                                                                        2     0   O   H   NHCbz                                    1154 imidazolin-2-ylamino                                                                        3     0   O   H   NHCbz                                    1155 tetrahydropyrimidin-                                                                        2     0   O   H   NHCbz                                         2-ylamino                                                                1156 tetrahydropyrimidin-                                                                        3     0   O   H   NHCbz                                         2-ylamino                                                                1157 imidazolin-2-ylamino                                                                        2     0   O   H   NHSO.sub.2 -n-Bu                         1158 imidazolin-2-ylamino                                                                        3     0   O   H   NHSO.sub.2 -n-Bu                         1159 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 -n-Bu                              2-ylamino                                                                1160 tetrahydropyrimidin-                                                                        3     0   O   H   NHSO.sub.2 -n-Bu                              2-ylamino                                                                1161 imidazolin-2-ylamino                                                                        3     0   S   H   NHCbz                                    1162 tetrahydropyrimidin-                                                                        3     0   S   H   NHCbz                                         2-ylamino                                                                1163 imidazolin-2-ylamino                                                                        3     0   S   H   NHSO.sub.2 -n-Bu                         1164 tetrahydropyrimidin-                                                                        3     0   S   H   NHSO.sub.2 -n-Bu                              2-ylamino                                                                1165 imidazolin-2-ylamino                                                                        3     0   O   Me  NHCbz                                    1166 tetrahydropyrimidin-                                                                        3     0   O   Me  NHSO.sub.2 Bu                                 2-ylamino                                                                1167 imidazolin-2-ylamino                                                                        3     0   O   Bn  NHCbz                                    1168 tetrahydropyrimidin-                                                                        3     0   O   Bn  NHCbz                                         2-ylamino                                                                1169 imidazolin-2-ylamino                                                                        3     0   O   Me  NHSO.sub.2 -n-Bu                         1170 tetrahydropyrimidin-                                                                        3     0   O   Me  NHCbz                                         2-ylamino                                                                1171 imidazolin-2-ylamino                                                                        3     0   O   Bn  NHSO.sub.2 -n-Bu                         1172 tetrahydropyrimidin-                                                                        3     0   O   Bn  NHCbz                                         2-ylamino                                                                1173 (4-oxoimidazolin-2-                                                                         2     0   O   H   NHCBz                                         yl)amino                                                                 1174 (4-oxoimidazolin-2-                                                                         3     0   O   H   NHCBz                                         yl)amino                                                                 1175 (4-oxoimidazolin-2-                                                                         2     0   O   H   NHCO.sub.2 -n-Bu                              yl)amino                                                                 1176 (4-oxoimidazolin-2-                                                                         3     0   O   H   NHCO.sub.2 -n-Bu                              yl)amino                                                                 1177 (4-oxoimidazolin-2-                                                                         2     0   O   H   NHSO.sub.2 Ph                                 yl)amino                                                                 1178 (4-oxoimidazolin-2-                                                                         3     0   O   H   NHSO.sub.2 Ph                                 yl)amino                                                                 1179 (4-oxoimidazolin-2-                                                                         2     0   O   H   NHSO.sub.2 -n-Bu                              yl)amino                                                                 1180 (4-oxoimidazolin-2-                                                                         3     0   O   H   NHSO.sub.2 -n-Bu                              yl)amino                                                                 1181 (4-oxotetrahydro-                                                                           3     0   O   H   NHCbz                                         pyrimidin-2-yl)amino                                                     1182 (4-oxotetrahydro-                                                                           3     0   O   H   NHCO.sub.2 -n-Bu                              pyrimidin-2-yl)amino                                                     1183 (4-oxotetrahydro-                                                                           3     0   O   H   NHSO.sub.2 Ph                                 pyrimidin-2-yl)amino                                                     1184 (4-oxotetrahydro-                                                                           3     0   O   H   NHSO.sub.2 -n-Bu                              pyrimidin-2-yl)amino                                                     1185 (4-oxoimidazolin-2-                                                                         3     0   S   H   NHCbz                                         yl)amino                                                                 1186 (4-oxoimidazolin-2-                                                                         3     0   S   H   NHSO.sub.2 -n-Bu                              yl)amino                                                                 1187 (4-oxotetrahydro-                                                                           3     0   S   H   NHCbz                                         pyrimidin-2-yl)amino                                                     1188 (4-oxotetrahydro-                                                                           3     0   S   H   NHSO.sub.2 -n-Bu                              pyrimidin-2-yl)amino                                                     1189 (4-oxoimidazolin-2-                                                                         3     0   O   Me  H                                             yl)amino                                                                 1190 (4-oxotetrahydro-                                                                           3     0   O   Me  H                                             pyrimidin-2-yl)amino                                                     1191 (4-oxoimidazolin-2-                                                                         3     0   O   Bn  H                                             yl)amino                                                                 ______________________________________                                        Ex.                                                                           No.  R.sup.1 -U    m     n   Q   R.sup.8                                                                           R.sup.9                                  ______________________________________                                        1192 (4-oxotetrahydro-                                                                           3     0   O   Bn  H                                             pyrimidin-2-yl)amino                                                     1193 (4-oxoimidazolin-2-                                                                         3     0   O   Me  NHCbz                                         yl)amino                                                                 1194 (4-oxotetrahydro-                                                                           3     0   O   Me  NHSO.sub.2 -n-Bu                              pyrimidin-2-yl)amino                                                     1195 (4-oxoimidazolin-2-                                                                         3     0   O   H   NHCbz                                         yl)amino                                                                 1196 (4-oxotetrahydro-                                                                           3     0   O   H   NHCbz                                         pyrimidin-2-yl)amino                                                     1197 imidazolin-2- 1     0   O   H   NHCbz                                         ylaminocarbonyl                                                          1198 imidazolin-2- 2     0   O   H   NHCbz                                         ylaminocarbonyl                                                          1199 tetrahydropyrimidin-                                                                        1     0   O   H   NHSO.sub.2 -n-Bu                              2-ylaminocarbonyl                                                        1200 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 -n-Bu                              2-ylaminocarbonyl                                                        1201 imidazolin-2- 2     0   O   H   NHCbz                                         ylaminocarbonyl                                                          1202 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 -n-Bu                              2-ylaminocarbonyl                                                        1203 imidazolin-2- 1     0   O   H   NHCO.sub.2 -n-Bu                              ylaminocarbonyl                                                          1204 imidazolin-2- 2     0   O   H   NHCO.sub.2 -n-Bu                              ylaminocarbonyl                                                          1205 tetrahydropyrimidin-                                                                        1     0   O   H   NHSO.sub.2 Ph                                 2-ylaminocarbonyl                                                        1206 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 Ph                                 2-ylaminocarbonyl                                                        1207 imidazolin-2- 2     0   O   Me  NHCbz                                         ylaminocarbonyl                                                          1208 tetrahydropyrimidin-                                                                        2     0   O   Me  NHSO.sub.2 -n-Bu                              2-ylaminocarbonyl                                                        1209 imidazolin-2- 2     0   O   Bn  H                                             ylaminocarbonyl                                                          1210 tetrahydropyrimidin-                                                                        2     0   O   Bn  H                                             2-ylaminocarbonyl                                                        1211 imidazolin-2- 2     0   O   Me  H                                             ylaminocarbonyl                                                          ______________________________________                                        Ex.                                                                           No.  R.sup.1 -U    m     n   G   R.sup.8                                                                           R.sup.9                                  ______________________________________                                        1212 tetrahydropyrimidin-                                                                        2     0   O   Me  H                                             2-ylaminocarbonyl                                                        1213 imidazolin-2- 2     0   O   H   NHCbz                                         ylaminocarbonyl                                                          1214 tetrahydropyrimidin-                                                                        2     0   O   H   NHCbz                                         2-ylaminocarbonyl                                                        1215 imidazolin-2- 2     0   O   H   NHSO.sub.2 -n-Bu                              ylaminocarbonyl                                                          1216 tetrahydropyrimidin-                                                                        2     0   O   H   NHSO.sub.2 -n-Bu                              2-ylaminocarbonyl                                                        1217 imidazolin-2- 2     0   S   Me  H                                             ylaminocarbonyl                                                          1218 tetrahydropyrimidin-                                                                        2     0   S   Bn  H                                             2-ylaminocarbonyl                                                        1219 imidazolin-2- 2     0   S   H   NHCbz                                         ylaminocarbonyl                                                          1220 tetrahydropyrimidin-                                                                        2     0   S   H   NHSO.sub.2 -n-Bu                              2-ylaminocarbonyl                                                        1221 imidazolin-2-ylamino                                                                        2     1   O   H   NHCbz                                    1222 imidazolin-2-ylamino                                                                        3     1   O   H   NHCbz                                    1223 tetrahydropyrimidin-                                                                        2     1   O   H   NHCbz                                         2-ylamino                                                                1224 tetrahydropyrimidin-                                                                        3     1   O   H   NHCbz                                         2-ylamino                                                                1225 imidazolin-2-ylamino                                                                        2     1   O   H   NHSO.sub.2 -n-Bu                         1226 imidazolin-2-ylamino                                                                        3     1   O   H   NHSO.sub.2 -n-Bu                         1227 tetrahydropyrimidin-                                                                        2     1   O   H   NHSO.sub.2 -n-Bu                              2-ylamino                                                                1228 tetrahydropyrimidin-                                                                        3     1   O   H   NHSO.sub.2 -n-Bu                              2-ylamino                                                                1229 imidazolin-2-ylamino                                                                        2     1   S   H   NHCbz                                    1230 imidazolin-2-ylamino                                                                        3     1   S   H   NHCbz                                    1231 tetrahydropyrimidin-                                                                        2     1   S   H   NHCbz                                         2-ylamino                                                                1232 tetrahydropyrimidin-                                                                        3     1   S   H   NHCbz                                         2-ylamino                                                                1233 imidazolin-2-ylamino                                                                        2     1   O   Me  H                                        1234 imidazolin-2-ylamino                                                                        3     1   O   Me  H                                        1235 tetrahydropyrimidin-                                                                        2     1   O   Bn  H                                             2-ylamino                                                                1236 tetrahydropyrimidin-                                                                        3     1   O   Bn  H                                             2-ylamino                                                                1237 imidazolin-2-ylamino                                                                        2     1   S   Me  H                                        1238 tetrahydropyrimidin-                                                                        2     1   S   Bn  H                                             2-ylamino                                                                1239 imidazolin-2-ylamino                                                                        2     1   O   Me  NHCbz                                    1240 tetrahydropyrimidin-                                                                        2     1   O   Me  NHCbz                                         2-ylamino                                                                1241 imidazolin-2-ylamino                                                                        2     1   O   H   NHCbz                                    1242 tetrahydropyrimidin-                                                                        2     1   O   H   NHCbz                                         2-ylamino                                                                1243 imidazolin-2-ylamino                                                                        3     1   O   H   NHCbz                                    1244 tetrahydropyrimidin-                                                                        3     1   O   H   NHCbz                                         2-ylamino                                                                1245 pyridin-2-ylamino                                                                           2     1   O   H   NHCbz                                    1246 imidazol-2-ylamino                                                                          2     1   O   H   NHCbz                                    1247 1,2,4-thiadiazol-5-                                                                         2     1   O   H   NHCbz                                         ylamino                                                                  1248 isoxazol-3-ylamino                                                                          2     1   O   H   NHCbz     H                              1249 oxazol-2-ylamino                                                                            2     1   O   H   NHCbz                                    1250 1,2,5-thiadiazol-3-                                                                         2     1   O   H   NHCbz                                         ylamino                                                                  1251 benzimidazol-2-                                                                             2     1   O   H   NHCbz                                         ylamino                                                                  1252 benzthiazol-2-                                                                              2     1   O   H   NHCbz                                         ylamino                                                                  1253 1,2-pyrazol-3-                                                                              2     1   O   H   NHCbz                                         ylamino                                                                  1254 1,2,4-triazol-5-                                                                            2     1   O   H   NHCbz                                         ylamino                                                                  1255 imidazol-4-ylamino                                                                          2     1   O   H   NHCbz                                    1256 1,3,4-oxadiazol-2-                                                                          2     1   O   H   NHCbz                                         ylamino                                                                  1257 1,2,4-thiadiazol-5-                                                                         2     1   O   H   NHCbz                                         ylamino                                                                  1258 1,2,4-thiadiazol-3-                                                                         2     1   O   H   NHCbz                                         ylamino                                                                  1259 1,2,5-oxadiazol-3-                                                                          2     1   O   H   NHCbz                                         ylamino                                                                  1260 1,2,4-oxadiazol-5-                                                                          2     1   O   H   NHCbz                                         ylamino                                                                  1261 1,2,4-oxadiazol-3-                                                                          2     1   O   H   NHCbz                                         ylamino                                                                  1262 pyridin-2-ylamino                                                                           3     0   O   H   NHCbz                                    1263 imidazol-2-ylamino                                                                          3     0   O   H   NHCbz                                    1264 1,2,4-thiadiazol-5-                                                                         3     0   O   H   NHCbz                                         ylamino                                                                  1265 isoxazol-3-ylamino                                                                          3     0   O   H   NHCbz                                    1266 oxazol-2-ylamino                                                                            3     0   O   H   NHCbz                                    1267 1,2,5-thiadiazol-3-                                                                         3     0   O   H   NHCbz                                         ylamino                                                                  1268 benzimidazol-2-                                                                             3     0   O   H   NHCbz                                         ylamino                                                                  1269 benzthiazol-2 3     0   O   H   NHCbz                                         ylamino                                                                  1270 1,2-pyrazol-3-                                                                              3     0   O   H   NHCbz                                         ylamino                                                                  1271 1,2,4-triazol-5-                                                                            3     0   O   H   NHCbz                                         ylamino                                                                  1272 imidazol-4-ylamino                                                                          3     0   O   H   NHCbz                                    1273 1,3,4-oxadiazol-2-                                                                          3     0   O   H   NHCbz                                         ylamino                                                                  1274 1,2,4-thiadiazol-5-                                                                         3     0   O   H   NHCbz                                         ylamino                                                                  1275 1,2,4-thiadiazol-3-                                                                         3     0   O   H   NHCbz                                         ylamino                                                                  1276 1,2,5-oxadiazol-3-                                                                          3     0   O   H   NHCbz                                         ylamino                                                                  1277 1,2,4-oxadiazol-5-                                                                          3     0   O   H   NHCbz                                         ylamino                                                                  1278 1,2,4-oxadiazol-3-                                                                          3     0   O   H   NHCbz                                         ylamino                                                                  1279 pyridin-2-ylamino                                                                           2     0   O   H   NHCbz                                    1280 imidazol-2-ylamino                                                                          2     0   O   H   NHCbz                                    1281 1,2,4-thiadiazol-5-                                                                         2     0   O   H   NHCbz                                         ylamino                                                                  1282 isoxazol-3-ylamino                                                                          2     0   O   H   NHCbz                                    1283 oxazol-2-ylamino                                                                            2     0   O   H   NHCbz                                    1284 1,2,5-thiadiazol-3-                                                                         2     0   O   H   NHCbz                                         ylamino                                                                  1285 benzimidazol-2-                                                                             2     0   O   H   NHCbz                                         ylamino                                                                  1286 benzthiazol-2-                                                                              2     0   O   H   NHCbz                                         ylamino                                                                  1287 1,2-pyrazol-3-                                                                              2     0   O   H   NHCbz                                         ylamino                                                                  1288 1,2,4-triazol-5-                                                                            2     0   O   H   NHCbz                                         ylamino                                                                  1289 imidazol-4-ylamino                                                                          2     0   O   H   NHCbz                                    1290 1,3,4-oxadiazol-2-                                                                          2     0   O   H   NHCbz                                         ylamino                                                                  1291 1,2,4-thiadiazol-5-                                                                         2     0   O   H   NHCbz                                         ylamino                                                                  1292 1,2,4-thiadiazol-3-                                                                         2     0   O   H   NHCbz                                         ylamino                                                                  1293 1,2,5-oxadiazol-3-                                                                          2     0   O   H   NHCbz                                         ylamino                                                                  1294 1,2,4-oxadiazol-5-                                                                          2     0   O   H   NHCbz                                         ylamino                                                                  1295 1,2,4-oxadiazol-3-                                                                          2     0   O   H   NHCbz                                         ylamino                                                                  ______________________________________                                    

UTILITY

The compounds of Formula I of the present invention possess activity asantagonists of integrins such as, for example, the α_(v) β₃ orvitronectin receptor, α_(v) β₅ or α₅ β1, and as such have utility in thetreatment and diagnosis of cell adhesion, angiogenic disorders,inflammation, bone degradation, cancer metastases, diabetic retinopathy,thrombosis, restenosis, macular degeneration, and other conditionsmediated by cell adhesion and/or cell migration and/or angiogenesis. Theintegrin antagonist activity of the compounds of the present inventionis demonstrated using assays which measure the binding of a specificintegrin to a native ligand, for example, using the ELISA assaydescribed below for the binding of vitronectin to the α_(v) β₃ receptor.

The compounds of the present invention possess selectivity for the α_(v)β₃ receptor relative to the GPIIb/IIIa receptor as demonstrated by theirlack of activity in standard assays of platelet aggregation, such as theplatelet aggregation assay described below.

One of the major roles of integrins in vivo is to mediate cellularinteractions with adjacent cells. Cell based adhesion assays can be usedto mimic these interactions in vitro. A cell based assay is morerepresentative of the in vivo situation than an ELISA since the receptoris maintained in membranes in the native state. The compounds of thepresent invention have activity in cell-based assays of adhesion, forexample as demonstrated in using the cell adhesion assays describedbelow.

The compounds of Formula I of the present invention may be useful forthe treatment or prevention of other diseases which involve celladhesion processes, including, but not limited to, osteoporosis,rheumatoid arthritis, autoimmune disorders, bone degradation, rheumatoidarthritis, asthma, allergies, adult respiratory distress syndrome, graftversus host disease, organ transplantation, septic shock, psoriasis,eczema, contact dermatitis, osteoarthritis, atherosclerosis, metastasis,wound healing, inflammatory bowel disease and other angiogenicdisorders.

The compounds of Formula I have the ability to suppress/inhibitangiogenesis in vivo, for example, as demonstrated using animal modelsof ocular neovascularization.

The compounds provided by this invention are also useful as standardsand reagents in determining the ability of a potential pharmaceutical toinhibit integrin-ligand binding. These may be provided in a commercialkit comprising a compound of this invention.

As used herein "μg" denotes microgram, "mg" denotes milligram, "g"denotes gram, "μL" denotes microliter, "mL" denotes milliliter, "L"denotes liter, "nM" denotes nanomolar, "μM" denotes micromolar, "mM"denotes millimolar, "M" denotes molar and "nm" denotes nanometer."Sigma" stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

The utility of the compounds of the present invention may be assessed bytesting in one or more of the following assays as described in detailbelow: Purified α_(v) β₃ (human placenta)--Vitronectin ELISA, α_(v) β₃-Vitronectin Binding Assay, Human Aortic Smooth Muscle Cell MigrationAssay, In Vivo Angiogenesis Model, Pig Restenosis Model, MouseRetinopathy Model. A compound of the present invention is considered tobe active if it has an IC₅₀ or K_(i) value of less than about 10 μM forthe inhibition of α_(v) β₃ -Vitronectin Binding Assay, with compoundspreferably having K_(i) values of less than about 0.1 μM. Compounds ofthe present invention are active in the α_(v) β₃ -Vitronectin BindingAssay as well as in cell-based assays of integrin adhesion mediated bythe α_(v) β₃ -receptor.

Purified α_(v) β₃ (human placenta)--Vitronectin ELISA

The α_(v) β₃ receptor was isolated from human placental extractsprepared using octylglucoside. The extracts were passed over an affinitycolumn composed of anti-α_(v) β₃ monoclonal antibody (LM609) to Affigel.The column was subsequently washed extensively at pH 7 and pH 4.5followed by elution at pH 3. The resulting sample was concentrated bywheat germ agglutinin chromatography to provide gave two bands on SDSgel which were confirmed as α_(v) β₃ by western blotting.

Affinity purified protein was diluted at different levels and plated to96 well plates. ELISA was performed using fixed concentration ofbiotinylated vitronectin (approximately 80 nM/well). This receptorpreparation contains the α_(v) β₃ with no detectable levels of α_(v) β₅according to the gel (α_(v) β₃) and according to effects of blockingantibodies for the α_(v) β₃ or α_(v) β₅ in the ELISA.

A submaximal concentration of biotinylated vitronectin was selectedbased on conc. response curve with fixed receptor conc. and variableconcentrations of biotinylated vitronectin.

α_(v) β₃ -Vitronectin Binding Assay

The purified receptor is diluted with coating buffer (20 mM Tris HCl,150 mM NaCl, 2.0 mM CaCl₂, 1.0 mM MgCl₂.6H₂ O, 1.0 mM MnCl₂.4H₂ O) andcoated (100 μL/well) on Costar (3590) high capacity binding platesovernight at 4° C. The coating solution is discarded and the plateswashed once with blocking/binding buffer (B/B buffer, 50 mM Tris HCl,100 mM NaCl, 2.0 mM CaCl₂,1.0 mM MgCl₂.6H₂ O,1.0 mM MnCl₂.4H₂ O).Receptor is then blocked (200 μL/well) with 3.5% BSA in B/B buffer for 2hours at room temperature. After washing once with 1.0% BSA in B/Bbuffer, biotinylated vitronectin (100 μL) and either inhibitor (11 μL)or B/B buffer w/1.0% BSA (11 μL)is added to each well. The plates areincubated 2 hours at room temperature. The plates are washed twice withB/B buffer and incubated 1 hour at room temperature with anti-biotinalkaline phosphatase (100 μL/well) in B/B buffer containing 1.0% BSA.The plates are washed twice with B/B buffer and alkaline phosphatasesubstrate (100 μL) is added. Color is developed at room temperature.Color development is stopped by addition of 2N NaOH (25 μL/well) andabsorbance is read at 405 nm. The IC₅₀ is the concentration of testsubstance needed to block 50% of the vitronectin binding to thereceptor.

Integrin Cell-Based Adhesion Assays

In the adhesion assays, a 96 well plate was coated with the ligand(i.e., fibrinogen) and incubated overnight at 4° C. The following day,the cells were harvested, washed and loaded with a fluorescent dye.Compounds and cells were added together and then were immediately addedto the coated plate. After incubation, loose cells are removed from theplate, and the plate (with adherent cells) is counted on a fluorometer.The ability of test compounds to inhibit cell adhesion by 50% is givenby the IC₅₀ value and represents a measure of potency of inhibition ofintegrin mediated binding. Compounds were tested for their ability toblock cell adhesion using assays specific for α_(v) β₃, α_(v) β₅ and α₅β₁ integrin interactions.

Platelet Aggregation Assay

Venous blood was obtained from anesthetized mongrel dogs or from healthyhuman donors who were drug- and aspirin-free for at least two weeksprior to blood collection. Blood was collected into citrated Vacutainertubes. The blood was centrifuged for 15 minutes at 150×g (850 RPM in aSorvall RT6000 Tabletop Centrifuge with H-1000 B rotor) at roomtemperature, and platelet-rich plasma (PRP) was removed. The remainingblood was centrifuged for 15 minutes at 1500×g (26,780 RPM) at roomtemperature, and platelet-poor plasma (PPP) was removed. Samples wereassayed on a PAP-4 Platelet Aggregation Profiler, using PPP as the blank(100% transmittance). 200 μL of PRP (5×10⁸ platelets/mL) were added toeach micro test tube, and transmittance was set to 0%. 20 μL of ADP (10μM) was added to each tube, and the aggregation profiles were plotted (%transmittance versus time). Test agent (20 μL) was added at differentconcentrations prior to the addition of the platelet agonist. Resultsare expressed as % inhibition of agonist-induced platelet aggregation.

Human Aortic Smooth Muscle Cell Migration Assay

A method for assessing α_(v) β₃ -mediated smooth muscle cell migrationand agents which inhibit α_(v) β₃ -mediated smooth muscle cell migrationis described in Liaw et al., J. Clin. Invest. (1995) 95: 713-724).

In Vivo Angiogenesis Model

A quantitative method for assessing angiogenesis and antiangiogenicagents is described in Passaniti et al., Laboratory Investigation (1992)67: 519-528

Pig Restenosis Model

A method for assessing restenosis and agents which inhibit restenosis isdescribed in Schwartz et al., J. Am. College of Cardiology (1992) 19:267-274.

Mouse Retinopathy Model

A method for assessing retinopathy and agents which inhibit retinopathyis described in Smith et al., Invest. Ophthal. & Visual Science (1994)35: 101-111.

Dosage and Formulation

The compounds of this invention can be administered by any means thatproduces contact of the active agent with the agent's site of action,the α_(v) β₃ integrin, in the body of a mammal. They can be administeredby any conventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents, such as a antiplatelet agent such asaspirin, piroxicam, or ticlopidine which are agonist-specific, or ananti-coagulant such as warfarin or heparin, or a thrombin inhibitor suchas a boropeptide, hirudin or argatroban, or a thrombolytic agent such astissue plasminogen activator, anistreplase, urokinase or streptokinase,or combinations thereof. The compounds of the invention, or compounds ofthe invention in combination with other therapeutic agents, can beadministered alone, but generally administered with a pharmaceuticalcarrier selected on the basis of the chosen route of administration andstandard pharmaceutical practice.

The dosage of the novel cyclic compounds of this invention administeredwill, of course, vary depending upon known factors, such as thepharmacodynamic characteristics of the particular agent and its mode androute of administration; the age, health and weight of the recipient;the nature and extent of the symptoms; the kind of concurrent treatment;the frequency of treatment; and the effect desired. A daily dosage ofactive ingredient can be expected to be about 0.001 to 10 milligrams perkilogram of body weight.

Dosage forms (compositions suitable for administration) contain fromabout 0.1 milligram to about 100 milligrams of active ingredient perunit. In these pharmaceutical compositions the active ingredient willordinarily be present in an amount of about 0.5-95% by weight based onthe total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, starch, cellulose derivatives, magnesium stearate,stearic acid, and the like. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient a cceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition , parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 10 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 10 milligrams of the active ingredient. The capsules arewashed and dried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit was 10 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings may beapplied to increase palatability or delay absorption.

The combination products of this invention, such as the novel α_(v) β₃antagonist compounds of this invention in combination with ananti-coagulant agent such as warfarin or heparin, or an anti-plateletagent such as aspirin, piroxicam or ticlopidine, or a thrombin inhibitorsuch as a boropeptide, hirudin or argatroban, or a thrombolytic agentsuch as tissue plasminogen activator, anistreplase, urokinase orstreptokinase, or combinations thereof, can be in any dosage form, suchas those described above, and can also be administered in various ways,as described above.

In a preferred embodiment, the combination products of the invention areformulated together, in a single dosage form (that is, combined togetherin one capsule, tablet, powder, or liquid, etc.). When the combinationproducts are not formulated together in a single dosage form, the α_(v)β₃ antagonist compounds of this invention and the anti-coagulant agent,anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent maybe administered at the same time (that is, together), or in any order,for example the compounds of this invention are administered first,followed by administration of the anti-coagulant agent, anti-plateletagent, thrombin inhibitor, and/or thrombolytic agent. When notadministered at the same time, preferably the administration of thecompound of this invention and any anti-coagulant agent, anti-plateletagent, thrombin inhibitor, and/or thrombolytic agent occurs less thanabout one hour apart, more preferably less than about 30 minutes apart,even more preferably less than about 15 minutes apart, and mostpreferably less than about 5 minutes apart. Preferably, administrationof the combination products of the invention is oral. The terms oralagent, oral inhibitor, oral compound, or the like, as used herein,denote compounds which may be orally administered. Although it ispreferable that the α_(v) β₃ antagonist compounds of this invention andthe anti-coagulant agent, anti-platelet agent, thrombin inhibitor,and/or thrombolytic agent are both administered in the same fashion(that is, for example, both orally), if desired, they may each beadministered in different fashions (that is, for example, one componentof the combination product may be administered orally, and anothercomponent may be administered intravenously). The dosage of thecombination products of the invention may vary depending upon variousfactors such as the pharmacodynamic characteristics of the particularagent and its mode and route of administration, the age, health andweight of the recipient, the nature and extent of the symptoms, the kindof concurrent treatment, the frequency of treatment, and the effectdesired, as described above.

As discussed above, where two or more of the foregoing therapeuticagents are combined or co-administered with the compounds of thisinvention, generally the amount of each component in a typical dailydosage and typical dosage form may be reduced relative to the usualdosage of the agent when administered alone, in view of the additive orsynergistic effect which would be obtained as a result of addition offurther agents in accordance with the present invention.

Particularly when provided as a single dosage form, the potential existsfor a chemical interaction between the combined active ingredients (forexample, a novel compound of this invention and an anti-coagulant suchas warfarin or heparin, or a novel compound of this invention and ananti-platelet agent such as aspirin, piroxicam or ticlopidine, or anovel compound of this invention and a thrombin inhibitor such as aboropeptide, hirudin or argatroban, or a novel compound of thisinvention and a thrombolytic agent such as tissue plasminogen activator,anistreplase, urokinase or streptokinase, or combinations thereof). Forthis reason, the preferred dosage forms of the combination products ofthis invention are formulated such that although the active ingredientsare combined in a single dosage form, the physical contact between theactive ingredients is minimized (that is, reduced).

In order to minimize contact, one embodiment of this invention where theproduct is orally administered provides for a combination productwherein one active ingredient is enteric coated. By enteric coating oneof the active ingredients, it is possible not only to minimize thecontact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. Anotherembodiment of this invention where oral administration is desiredprovides for a combination product wherein one of the active ingredientsis coated with a sustained-release material which effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

Dosage forms of the combination products of the present inventionwherein one active ingredient is enteric coated can be in the form oftablets such that the enteric coated component and the other activeingredient are blended together and then compressed into a tablet orsuch that the enteric coated component is compressed into one tabletlayer and the other active ingredient is compressed into an additionallayer. Optionally, in order to further separate the two layers, one ormore placebo layers may be present such that the placebo layer isbetween the layers of active ingredients. In addition, dosage forms ofthe present invention can be in the form of capsules wherein one activeingredient is compressed into a tablet or in the form of a plurality ofmicrotablets, particles, granules or non-perils, which are then entericcoated. These enteric coated microtablets, particles, granules ornon-perils are then placed into a capsule or compressed into a capsulealong with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Pharmaceutical kits useful in, for example, the inhibition of thrombusformation, the prevention of blood clots, and/or the treatment ofthromboembolic disorders, which comprise a therapeutically effectiveamount of a compound according to the method of the present inventionalong with a therapeutically effective amount of an anti-coagulant agentsuch as warfarin or heparin, or an antiplatelet agent such as aspirin,piroxicam or ticlopidine, or a thrombin inhibitor such as a boropeptide,hirudin or argatroban, or a thrombolytic agent such as tissueplasminogen activator, anistreplase, urokinase or streptokinase, orcombinations thereof, in one or more sterile containers, are also withinthe ambit of the present invention. Sterilization of the container maybe carried out using conventional sterilization methodology well knownto those skilled in the art. The sterile containers of materials maycomprise separate containers, or one or more multi-part containers, asexemplified by the UNIVIAL™ two-part container (available from AbbottLabs, Chicago, Ill.), as desired. The compounds according to the methodof the invention and the anti-coagulant agent, anti-platelet agent,thrombin inhibitor, thrombolytic agent, and/or combinations thereof, maybe separate, or combined into a single dosage form as described above.Such kits may further include, if desired, one or more of variousconventional pharmaceutical kit components, such as for example, one ormore pharmaceutically acceptable carriers, additional vials for mixingthe components, etc., as will be readily apparent to those skilled inthe art. Instructions, either as inserts or as labels, indicatingquantities of the components to be administered, guidelines foradministration, and/or guidelines for mixing the components, may also beincluded in the kit.

What is claimed is:
 1. A compound of the formula ##STR21## orpharmaceutically acceptable salts thereof, wherein: R¹ is selected from:##STR22## G is selected from O or S; R² and R³ are independentlyselected from: H, C₁ -C₄ alkoxy, NR¹¹ R¹², ═NR¹², halogen, NO₂, CN, CF₃,C₁ -C₆ alkyl, C₃ -C₆ alkenyl, C₃ -C₇ cycloalkyl, C₄ -C₁₁cycloalkylalkyl, C₆ -C₁₀ aryl, C₇ -C₁₁ arylalkyl, C₂ -C₇ alkylcarbonyl,or C₇ -C₁₁ arylcarbonyl;U is selected from:--(CH₂)_(n) --, --(CH₂)_(n)N(R¹²)(CH₂)_(m) --, or --(CH₂)_(n) NHNH(CH₂)_(m) --; V is selectedfrom:--(CH₂)_(n) --, --(C₁ -C₆ alkylene)--Q--, substituted with 0-3groups independently selected from R¹³, --(C₂ -C₇ alkenylene)--Q--,substituted with 0-3 groups independently selected from R¹³, --(C₂ -C₇alkynylene)--Q--, substituted with 0-3 groups independently selectedfrom R¹³, or --(phenyl)--Q--, wherein said phenyl is substituted with0-2 groups independently selected from R¹³ ; Q is selectedfrom:--(CH₂)_(n) --, --(CH₂)_(n) O(CH₂)_(m) --, or --(CH₂)_(n)N(R¹²)(CH₂)_(m) --; W is selected from:--(CH₂)_(q) C(═O)N(R¹⁰)--, --SCH₂C(═O)N(R¹⁰)--, or --C(═O)--N(R¹⁰)--(CH₂)_(q) --; X is selectedfrom:--(CH₂)_(q) --CH(R⁸)--CH(R⁹) --(CH₂)_(q) --CH(CH₂ R⁹) or --CH₂ --;R⁵ is selected from: H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃-C₇ cycloalkyl, C₇ -C₁₄ bicycloalkyl, hydroxy, C₁ -C₆ alkoxy, C₁ -C₆alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, nitro, C₁ -C₆alkylcarbonyl, C₆ -C₁₀ aryl, --N(R¹¹)R¹² ; halo, CF₃, CN, C₁ -C₆alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl; R⁶ isselected from:H, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ alkoxy, nitro, C₁ -C₆alkylcarbonyl, --N(R¹¹)R¹², cyano, halo, --S(O)mR¹⁰, CO₂ R¹⁰, OR¹⁰,C₆ toC₁₀ aryl optionally substituted with 1-3 groups selected from halogen,C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) Me, or --NMe₂ ;methylenedioxy when R⁶ is a substituent on aryl, or a heterocyclic ringsystem selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl,pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl,quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl,tetrahydrofuranyl, pyranyl, 3H-indolyl, carbazolyl, pyrrolidinyl,piperidinyl, isoxazolinyl, isoxazolyl, or morpholinyl; R⁸ is selectedfrom:H, C₁ -C₁₀ alkyl, substituted with 0-3 R⁶, C₂ -C₁₀ alkenyl,substituted with 0-3 R⁶, C₂ -C₁₀ alkynyl, substituted with 0-3 R⁶, C₃-C₈ cycloalkyl, substituted with 0-3 R⁶, C₅ -C₆ cycloalkenyl,substituted with 0-3 R⁶, aryl, substituted with 0-3 R⁶, a heterocyclicring system selected from pyridinyl, furanyl, thiazolyl, thienyl,pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl,indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl,tetrahydrofuranyl, pyranyl, 3H-indolyl, carbazolyl, pyrrolidinyl,piperidinyl, isoxazolinyl, isoxazolyl or morpholinyl; R⁹ is selectedfrom: H, hydroxy, C₁ -C₁₀ alkoxy, N(R¹⁰)R¹¹, or --N(R¹⁶)R¹⁷ ; R¹⁰ isselected from H or C₁ -C₁₀ alkyl substituted with 0-2 R⁵ ; R¹¹ isselected from hydrogen, hydroxy, C₁ to C₈ alkyl, C₃ -C₆ alkenyl, C₃ toC₁₁ cycloalkyl, C₄ to C₁₁ cycloalkylmethyl, C₁ -C₆ alkoxy, benzyloxy, C₆to C₁₀ aryl, heteroaryl, heteroarylalkyl, C₇ to C₁₁ arylalkyl,adamantylmethyl, or C₁ -C₁₀ alkyl substituted with 0-2 R⁵;alternatively, R¹⁰ and R¹¹ when both are substituents on the samenitrogen atom (as in --NR¹⁰ R¹¹) can be taken together with the nitrogenatom to which they are attached to form a heterocycle selected from:3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl; saidheterocycle being optionally substituted with 1-3 groups selected from:C₁ -C₆ alkyl, C₆ -C₁₀ aryl, heteroaryl, C₇ -C₁₁ arylalkyl, C₁ -C₆alkylcarbonyl, C₃ -C₇ cycloalkylcarbonyl, C₁ -C₆ alkoxycarbonyl, C₇ -C₁₁arylalkoxycarbonyl, C₁ -C₆ alkylsulfonyl or C₆ -C₁₀ arylsulfonyl; R¹² isselected from:H, C₁ -C₆ alkyl, C₁ -C₄ alkoxycarbonyl, C₁ -C₆alkylcarbonyl, C₁ -C₆ alkylsulfonyl, aryl(C₁ -C₄ alkyl)sulfonyl,arylsulfonyl, aryl, heteroarylcarbonyl, or heteroarylalkylcarbonyl,wherein said aryl groups are substituted with 0-3 substituents selectedfrom the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃,and NO₂ ; R¹³ is selected from H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁ -C₁₀ alkoxy, aryl, heteroaryl or C₁ -C₁₀alkoxycarbonyl, CO₂ R¹⁰ or --C(═O)N(R¹⁰)R¹¹ ; R¹⁶ is selectedfrom:--C(═O)--O--R^(18a), --C(═O)--R^(18b), --SO₂ --R^(18a), --SO₂--N(18^(b))₂ ; R¹⁷ is selected from H or C₁ -C₄ alkyl; R^(18a) isselected from:C₁ -C₈ alkyl substituted with 0-2 R¹⁹, C₂ -C₈ alkenylsubstituted with 0-2 R¹⁹, C₂ -C₈ alkynyl substituted with 0-2 R¹⁹, C₃-C₈ cycloalkyl substituted with 0-2 R¹⁹, aryl substituted with 0-4 R¹⁹,aryl(C₁ -C₆ alkyl)- substituted with 0-4 R¹⁹, a heterocyclic ring systemselected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl,pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl,quinolinyl, isoquinolinyl, isoxazolinyl, isoxazolyl, benzimidazolyl,piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl,carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, saidheterocyclic ring being substituted with 0-4 R¹⁹ ; C₁ -C₆ alkylsubstituted with a heterocyclic ring system selected from pyridinyl,furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,isoxazolinyl, isoxazolyl, benzofuranyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl,pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl,indolinyl, or morpholinyl, said heterocyclic ring being substituted with0-4 R¹⁹ ; R^(18b) is selected from R^(18a) or H; R¹⁹ is selected from:H, halogen, CF₃, CN, NO₂, NR¹¹ R¹², C₁ -C₈ alkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, C₃ -C₁₁ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, aryl, aryl(C₁ -C₆alkyl)--, C₁ -C₆ alkoxy, or C₁ -C₄ alkoxycarbonyl; R²⁰ is selectedfrom:hydroxy; C₁ to C₁₀ alkoxy; methylcarbonyloxymethoxy-,ethylcarbonyloxymethoxy-, t-butylcarbonyloxymethoxy-,cyclohexylcarbonyloxymethoxy-, 1-(methylcarbonyloxy)ethoxy-,1-(ethylcarbonyloxy)ethoxy-, 1-(t-butylcarbonyloxy)ethoxy-,1-(cyclohexylcarbonyloxy)ethoxy-, i-propyloxycarbonyloxymethoxy-,t-butyloxycarbonyloxymethoxy-, 1-(i-propyloxycarbonyloxy)ethoxy-,1-(cyclohexyloxycarbonyloxy)ethoxy-, 1-(t-butyloxycarbonyloxy)ethoxy-,dimethylaminoethoxy-, diethylaminoethoxy-,(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-,1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-, R²¹ is selected from C₁ -C₈alkyl, C₂ -C₆ alkenyl, C₃ -C₁₁, cycloalkyl, C₄ -C₁₁ cycloalkylmethyl, C₆-C₁₀ aryl, C₇ -C₁₁ arylalkyl, or C₁ -C₁₀ alkyl substituted with 0-2 R⁵;m is 0-2; n is 0-2; p is 0-2; q is 0-1; and r is 0-2; with the provisothat when V is -(phenyl)--Q--, then either: U is not a direct bond or Qis not a direct bond.
 2. A compound of claim 1 selected from the groupconsistingof:2(S)-Benzyloxycarbonylamino-3-[[2-[4-[N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt2(S)-(2,4,6-Trimethylphenylsulfonyl)amino-3-[[2-[4-[N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt2(S)-(1-Naphthalenesulfonyl)amino-3-[[2-[4-[N-(pyridin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionicacid TFA salt.
 3. A pharmaceutical composition comprising apharmaceutical carrier and a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt from thereof.4. A pharmaceutical composition comprising a pharmaceutical carrier anda therapeutically effective amount of a compound of claim 2 or apharmaceutically acceptable salt form thereof.
 5. A method in inhibitingthe aggregation of blood platelets which comprises administering to ahost in need of such inhibition a therapeutically effective amount of acompound of claim
 1. 6. A method of inhibiting the aggregation of bloodplatelets which comprises administering to a host in need of suchinhibition a therapeutically effective amount of a compound of claim 2.7. A method of treating thromboembolic disorders selected from thrombusor embolus formation, harmful platelet aggrgation, reocclusion followingthrombolysis, reperfusion injury, restenosis, atherosclerosis, stroke,myocardial infarction, and unstable angina, which comprisesadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound of claim
 1. 8. A method of treatingthromboembolic disorders selected from thrombus or embolus formation,harmful platelet aggregaion, reocclusion following thrombolysis,reperfusion injury, restenosis, atherosclerosis, stroke myocardialinfarction, and unstable angina, which comprises administering to a hostin need of such treatment a therapeutically effective amount of acompound of claim 2.